Reviewing the FDA guidance for Data Integrity and Compliance With CGMP

The “Why”:
Before we jump in to the details of “data integrity”, I strongly believe that doing the right thing (to comply with the FDA guidance for Data Integrity) is a much more cost-efficient approach for the business. This is supported by the following.

Data Integrity and Compliance is not a new fad and it is here to stay. Historical statistics revelas that 30, 27 and 33 warning letters relating to data integrity were issued in 2016, 2015 and 2014 respectively (see footnote 1).

It is costly to remediate data integrity issues cited in warning letters. Reviewing 5 of the recent warning letters (see footnote 2), it is clear that the remediation are very costly, prescriptive and consistent. For instance, one of the many required responses in all the 5 warning letters is:
“…An assessment of the extent of data integrity deficiencies at your facility. Identify omissions, alterations, deletions, record destruction, non-contemporaneous record completion, and other deficiencies. Describe all parts of your facility’s operations in which you discovered data integrity lapses…”

Thus, it is more cost-effective to do it right (proactive) than to try and correct it via a warning letter (reactive).

The “What”:
Now, first thing first, what is “data integrity”? Per the latest guidance (see footnote 3) published in Apr-2016, it is stated, “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).” It further references the ALCOA as follows.

A – Attributable – see §§ 211.101(d), 211.122, 211.186, 211.188(b)(11), and 212.50(c)(10);
L – Legible – see §§ 211.180(e) and 212.110(b);
C – Contemporaneously recorded (at the time of performance) – see §§ 211.100(b) and 211.160(a);
O – Original or a true copy see §§ 211.180 and 211.194(a);
A – Accurate – see §§ 211.22(a), 211.68, 211.188, and 212.60(g).

For this post, let’s just review the first “A” in ALCOA, which is “Attributable”.

The “Attributable” bottomline – No shared account:
My opinion is there is no reasonable justifications (other than equipment constraint, which would require procedural controls then), for a shared userid approach in any scenerio, to meet this requirement. A search in the eCFR reveals the lengthy text below (see footnote 4), which in essence, points to the IT practice of unique identification of userids. Having a unique owner identified and documented to a unique userid in computerized system will ensure that every action (i.e. create / modify / delete) relating to GMP data can be traced (always) to a unique person in the organization.

Hope this gives a quick overview of the FDA guidance for Data Integrity.

Do contact me, if you like a more detailed discussion for your organization’s needs with regards to data integrity.

Warm regards,
Fu Chin, Lim
Principal Consultant
Biopharma IT Consulting Pte Ltd
Tel: +65 97770919
flim@biopitc.com

Footnotes:

(1) The statistics is compiled via a search for “data integrity” in the warning letters section of the FDA website listed below:
https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/default.htm

(2) The following are the five warning letters reviewed:
https://www.fda.gov/iceci/enforcementactions/warningletters/2017/ucm543347.htm
https://www.fda.gov/iceci/enforcementactions/warningletters/2017/ucm538068.htm
https://www.fda.gov/iceci/enforcementactions/warningletters/2016/ucm525640.htm
https://www.fda.gov/iceci/enforcementactions/warningletters/2017/ucm536811.htm
https://www.fda.gov/iceci/enforcementactions/warningletters/2016/ucm534983.htm

(3) Data Integrity and Compliance With Current Good Manufacturing Practice Guidance for Industry, issued on 04-14-2016 is available at the following:
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM495891

(4) The following are extracted from the eCFR website per reference in the guidance in note (3) above. A – Attributable – see §§ 211.101(d), 211.122, 211.186, 211.188(b)(11), and 212.50(c)(10);

– 211.101(d) – Charge-in of components
(d) “Each component shall either be added to the batch by one person and verified by a second person or, if the components are added by automated equipment under §211.68, only verified by one person.”

– 211.122 – Materials examination and usage criteria.
(a) There shall be written procedures describing in sufficient detail the receipt, identification, storage, handling, sampling, examination, and/or testing of labeling and packaging materials; such written procedures shall be followed. Labeling and packaging materials shall be representatively sampled, and examined or tested upon receipt and before use in packaging or labeling of a drug product.
(b) Any labeling or packaging materials meeting appropriate written specifications may be approved and released for use.
Any labeling or packaging materials that do not meet such specifications shall be rejected to prevent their use in operations for which they are unsuitable.
(c) Records shall be maintained for each shipment received of each different labeling and packaging material indicating receipt, examination or testing, and whether accepted or rejected.
(d) Labels and other labeling materials for each different drug product, strength, dosage form, or quantity of contents shall be stored separately with suitable identification. Access to the storage area shall be limited to authorized personnel.
(e) Obsolete and outdated labels, labeling, and other packaging materials shall be destroyed.
(f) Use of gang-printed labeling for different drug products, or different strengths or net contents of the same drug product, is prohibited unless the labeling from gang-printed sheets is adequately differentiated by size, shape, or color.
(g) If cut labeling is used for immediate container labels, individual unit cartons, or multiunit cartons containing immediate containers that are not packaged in individual unit cartons, packaging and labeling operations shall include one of the following special control procedures:
(1) Dedication of labeling and packaging lines to each different strength of each different drug product;
(2) Use of appropriate electronic or electromechanical equipment to conduct a 100-percent examination for correct labeling during or after completion of finishing operations; or
(3) Use of visual inspection to conduct a 100-percent examination for correct labeling during or after completion of finishing operations for hand-applied labeling. Such examination shall be performed by one person and independently verified by a second person.
(4) Use of any automated technique, including differentiation by labeling size and shape, that physically prevents incorrect labeling from being processed by labeling and packaging equipment.
(h) Printing devices on, or associated with, manufacturing lines used to imprint labeling upon the drug product unit label
or case shall be monitored to assure that all imprinting conforms to the print specified in the batch production record.

– 211.186 – Master production and control records.
(a) To assure uniformity from batch to batch, master production and control records for each drug product, including each batch size thereof, shall be prepared, dated, and signed (full signature, handwritten) by one person and independently checked, dated, and signed by a second person. The preparation of master production and control records shall be described in a written procedure and such written procedure shall be followed.
(b) Master production and control records shall include:
(1) The name and strength of the product and a description of the dosage form;
(2) The name and weight or measure of each active ingredient per dosage unit or per unit of weight or measure of the drug product, and a statement of the total weight or measure of any dosage unit;
(3) A complete list of components designated by names or codes sufficiently specific to indicate any special quality characteristic;
(4) An accurate statement of the weight or measure of each component, using the same weight system (metric, avoirdupois, or apothecary) for each component. Reasonable variations may be permitted, however, in the amount of components necessary for the preparation in the dosage form, provided they are justified in the master production and control records;
(5) A statement concerning any calculated excess of component;
(6) A statement of theoretical weight or measure at appropriate phases of processing;
(7) A statement of theoretical yield, including the maximum and minimum percentages of theoretical yield beyond which investigation according to §211.192 is required;
(8) A description of the drug product containers, closures, and packaging materials, including a specimen or copy of each label and all other labeling signed and dated by the person or persons responsible for approval of such labeling;
(9) Complete manufacturing and control instructions, sampling and testing procedures, specifications, special notations, and precautions to be followed.

– 211.188(b)(11) – Batch production and control records.
(b) Documentation that each significant step in the manufacture, processing, packing, or holding of the batch was accomplished, including:
(11) Identification of the persons performing and directly supervising or checking each significant step in the operation, or if a significant step in the operation is performed by automated equipment under §211.68, the identification of the person checking the significant step performed by the automated equipment.

– 212.50(c)(10) – Production and Process Controls
(c) Batch production and control records. Each time a batch of a PET drug is produced, a unique batch production and control record must be created. The batch production record must include the following information:
(10) Initials or signatures of persons performing or checking each significant step in the operation;