Data Integrity As Per 21 CFR - You Should Know Now - Pharma Times Now - Pharmaceutical Industry and Regulatory Affairs

The US FDA is seriously probing into the data integrity issues all over the world. Even though the requirements for data integrity was established many years back, in the 21 CFR, the pharmaceutical industry is far behind in the implementation of those regulations even today. There may be so many reasons for the delayed implementation of it, but the cost paying is beyond the industry's expectations. The past horrible experiences of adulterated drugs, leaving no way to the regulatory agencies but to enforce the regulations. The public is not ready for one more disaster.

Is The Data Integrity An Essential Requirement In the Pharmaceutical Industry?

The modern computer technology, bringing revolutionary changes in the pharmaceutical industry. The industry is slowly paving its way towards the digital platforms to boost up its manufacturing activities. This is inevitable to meet the changing needs of the modern world.

Digital world means a stack of information stored electronically, which we call it an electronic record in our daily life. Today, the electronic data has become a critical business factor and health indicator of the pharmaceutical industry.

The utilization of digital technology increased in considerable amount in many parts of manufacturing and research activities. As a result, along with the paper records, electronic records also has become an integrated part of the batch production record and a critical measure in deciding the medicines' quality. Of course, medicines are for patients.

The patient is the centric force for both pharmaceutical industry and regulatory agencies because protection of public health is their primary responsibility. Public health is connected with the degree of quality of medicines. For the assessment of the quality of medicines, regulators majorly depend upon the data available and shown by the firms at the time of inspection. The data may exist either in paper format or electronic format.

Data has so much importance in the industry since the decision-making solely depends upon the data. The accuracy of the information, which has been written into both paper and electronic formats, is a major factor to consider in the drug release. Thus, the integrity of the data plays a chief role in medicines' quality.

In this context, to bring the safest medicines into the market, governments all over the world are enforcing some rules and regulations regarding the data generation and its management. Among such regulations, 21 CFR is the foremost one to mention as the whole pharmaceutical industry is considering it as an ideal regulatory system of the current times.

What Is 21 CFR?

The United States of America has a set of general and permanent rules to drive the country's administration. All these rules are codified under the name of "The Code of Federal Regulations (CFR)". This CFR is published annually in the Federal Register (FR) by the executive departments and agencies of the US Federal Government.

The Code of Federal Regulations is divided into 50 titles. Each title represents one area of administration and subject to federal regulation.The titles further divided into chapters, parts, sections and paragraphs.

21 CFR: This indicates the 21st Title "Food and Drugs" in "The Code of Federal Regulations (CFR)". As mentioned above, this also has divided into chapters, parts, sections and paragraphs.The details are:

Title 21 Food and Drugs

Chapters	Parts	Regulatory Entity
Chapter-I	1 - 1299	Food and Drug Administration, Departments of Health and Human Services
Chapter-II	1300 - 1399	Drug Enforcement Administration, Department of Justice
Chapter-III	1400 - 1499	Office of National Drug Control Policy

Regulations applicable to drugs with respect to Current good manufacturing practices (cGMP) are:

Part 210 - Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs;
General

Part 211 - Current Good Manufacturing Practice for Finished Pharmaceuticals;

Part 212 - Current Good Manufacturing Practice for Positron Emission Tomography Drugs

Part 225 - Current Good Manufacturing Practice for Medicated Feeds

Part 226 - Current Good Manufacturing Practice for Type A Medicated Articles

Part 600 - Biological Products: General

Part 680 - Additional Standards for Miscellaneous Products

Part 1271 - Human Cells, Tissues, and Cellular and Tissue-based Products

All the pharmaceutical companies which are selling and exporting medicinal drugs to the United States of America have to comply with the rules and regulations described in Title 21, Food and Drugs.

What Is Data As Per 21 CFR?

The main purpose of the 21 CFR is to ensure the food and drugs, which flows into the market for public use, are meeting the quality and purity characteristics and safe to consume. To fulfil this aim, a lot of regulations has been created by the regulatory agencies to control the manufacturing activities and adulterated drugs.

The firms should record all the activities performed to produce a product. Manufacturers should compose all the data, in such a way that, the records must reconstruct the whole process followed in the manufacture of a particular product. These records may be generated either in the paper format or in an electronic format. It doesn't matter. Both come under the scope of "cGMP record" and subject to the law.

In the pharmaceutical industry, data is generated and recorded during the manufacture, processing, packing, or holding of a drug. This data must be reliable and accurate. The following records are required as per the 21 CFR.

Records required as per the 21 CFR

#Serial	Part	Section	Paragraph	Record
1	Subpart-B	Sec. 211.25	a	Documents of role and responsibilities of employees.
2	Subpart-B	Sec. 211.25	a, b	Education, training, and experience records of the employees.
3	Subpart-B	Sec. 211.28	c	List of authorized personnel allowed into limited-access areas.
4	Subpart-B	Sec. 211.34	-	If you have engaged any consultant: education, training, and experience records should be available along with name, address and type of service they provide.
5	Subpart-D	Sec. 211.67	b	Equipment cleaning record; Equipment maintenance records.
6	Subpart-D	Sec. 211.68	a	Routine calibration of automatic, mechanical, or electronic equipment or other types of equipment.
7	Subpart-D	Sec. 211.68	b	Change history of Master production and control records.
8	Subpart-D	Sec. 211.68	b	A copy (backup file) of data entered into the computer.
9	Subpart-D	Sec. 211.68	b	Validation data of automated processes.
10	Subpart-D	Sec. 211.68	b	Hard copies that prove the backup data is exact and complete.
11	Subpart-D	Sec. 211.68	b	Tapes or microfilms that assure the backup data is exact and complete.
12	Subpart-E	Sec. 211.80	a	Records of containers and closures. Details shall include receipt, storage, sampling, testing and approval/rejection.
13	Subpart-F	Sec. 211.100	b	Details of batch production and process controls executed; record of any deviations from the written procedures.
14	Subpart-F	Sec. 211.103	-	Calculation of yield.
15	Subpart-F	Sec. 211.105	b	List of equipment along with the identification number which shall be recorded in the batch production record.
16	Subpart-F	Sec. 211.110	a	Details of in-process controls and tests; validation records of manufacturing processes.
17	Subpart-F	Sec. 211.111	-	Details of each batch production time and deviations from the established time.
18	Subpart-F	Sec. 211.113	b	Validation data of all aseptic and sterilization processes.
19	Subpart-F	Sec. 211.115	a	Complete records of reprocessed batches.
20	Subpart-G	Sec. 211.122	a	Full records of labelling and packaging materials.
21	Subpart-H	Sec. 211.142	b	Records of temperature and humidity at warehouses where drug products are stored.
22	Subpart-H	Sec. 211.150	b	Records of drug distribution; this includes return goods also.
23	Subpart-I	Sec. 211.160	b	Calibration or performance verification records of instruments, gauges, recording devices and apparatus.
24	Subpart-I	Sec. 211.165	b	Records of sampling and testing of each batch of drug product.
25	Subpart-I	Sec. 211.165	e	Validation documents of analytical test methods.
26	Subpart-I	Sec. 211.166	-	Records of stability testing.
27	Subpart-I	Sec. 211.170	-	Details of reserve samples and observations during the quality review.
28	Subpart-I	Sec. 211.173	-	Details of laboratory animals used in the testing.
29	Subpart-I	Sec. 211.176	-	Records of Penicillin contaminated drugs if any.
30	Subpart-J	Sec. 211.182	-	Logs of individual equipment.
31	Subpart-J	Sec. 211.184	c	An Individual record of each component, container and closure.
32	Subpart-J	Sec. 211.184	c	Reconciliation details of each component, container and closure.
33	Subpart-J	Sec. 211.198	b	Records of complaints received and actions taken.

The records are not limited to the above-mentioned ones. All the records, which are produced and used in the manufacture of a drug product or drug substance, are cGMP records. There are no exceptions.

What Is Data Integrity As Per 21 CFR?

I hope you have got the idea, from the above discussion, what the data means in the pharmaceutical industry. Now we have to look into the existence of the data. Records hold the data and facilitate us to make decisions. We can generate the records in two formats; paper and electronic. In some occasions, it could be in the hybrid form, i.e., a combination of both paper and electronic records.

Data integrity w.r.t., paper records

You may know that the majority of the records are generated in the paper format in the industry. The Pharma industry is not yet implemented complete automation in the manufacturing plants. Companies are still relying on paper documentation for routine production activities.

A paper record exists in a static record format, i.e., once the paper record is generated by a person or instrument, there will be no further interaction with its content by the user.

Accuracy and quality of paper records are dependent on the person's behavioral integrity and on the performance of the instrument used for the purpose. Hence, a lot of controls are imposed on the industry to protect the quality of a product.

The integrity of your paper records is in question when the records are :
- produced as an output from the non-calibrated instruments and gauges.
- generated using uncontrolled loose sheets.
- not verified by a second competent person.
- overwritten multiple times and there is no acknowledgement on it.
- manipulated by changing the numerical values in an unacceptable way.
- not restricted by a version control system.
- recreated by putting the backdate to hide failures or mistakes.
- the printouts obtained from a non-validated software.
- not recorded at the time of performance, but transcribed from a rough paper.
- not having proper identification details of their origin, i.e., it is unknown which task 's results the data
represent.
- recorded on an unapproved format by quality unit.
- generated using a pencil (where the performer has to write the data in the blank format) at the first instance
and later on rewritten the details with a pen by erasing the previous pencil entries.
- generated transcribing the data from mock sheets.
- found as intentionally excluded ones from cGMP records.

Data integrity w.r.t., electronic records

Technology is slowly creeping into the pharmaceutical industry. Even though it is not fully implemented in manufacturing activities, warehouse and laboratories are using it in an extensive way. These departments make decisions to release a batch based on the electronic records generated through various transactions.

Especially its role in the Quality control laboratory is very crucial. Multiple equipment and multiple software are used in the testing of materials in the laboratory. As a consequence, a lot of data generates in the analytical testing process which further is used in the decision making of batch release.

Similarly, in the manufacturing unit also, many software is used as part of process automation. It ranges from a simple program used to monitor temperatures to complicated software such as eBPR.

An electronic record exists in a dynamic record format, i.e., it allows user interaction with the record content even after the generation of the record.

Electronic records which are part of cGMP must be maintained as per Part 11, Electronic Records; Electronic Signatures — Scope and Application. All electronic records and electronic signatures, which are generated as part of predicate rule requirements, would fall under the scope of 21 CFR Part 11.

Predicate rules are requirements declared in 21 CFR Food and Drug Regulations. They provide clarity on which records to be maintained as per law. They also give directions on the submission of records to the regulatory agency.

The integrity of your electronic record is in question when the record is:
- not complete, i.e., a complete set of details are not retained.
- not consistent, i.e., data is not self-consistent.
- not accurate, i.e., it is not generated by a trained and qualified person;
generated by using non-validated software or non-calibrated instrument.
- not attributable to the user who is responsible for generating the data.
- not legible and permanent, i.e., the information is not readable and cannot be used for any purpose.
- not contemporaneously recorded.
- not original, i.e., not the first capture of information.
- not a true copy of the original data.
- not contained metadata.
- not contained audit trail data, i.e., the record does not contain its chronological history.
- generated using shared login accounts.
- generated by using non-validated software or computer program.
- generated by the software which has no access control.
- generated by the software which allows the user to modify and delete the data.
- not accessible for the review.
- found deleted which should be the part of cGMP data.
- reprocessed but not documented the justification.

Refer US FDA Guidance for Industry"Data Integrity and Compliance With CGMP"for more details.

Consequences Of Breach Of Data Integrity

A Breach in the integrity of data leads to severe regulatory actions. The loss occurring to the industry due this issue is very huge. Already you are seeing the situation of the companies which have received warning letters. They are struggling like anything to come out of the issue. Warning letter represents only one of the regulatory actions. There are many other actions too. Let us go through all the consequences of the breach of data integrity.

1	Regulatory actions such as warning letters, untitled letters, import alerts, consent decrees, seizures and injunctions may be imposed on the firms.
2	Huge loss of time, money and resources can kill the company's performance.
3	It takes a great length of time (months and years) to settle the things with regulatory bodies.
4	Companies will lose the credibility and reputation.
5	A single regulatory action from any one country will ruin the trust of all other regulatory bodies in the world on the subjected pharmaceutical company.
6	Company's wealth will be evaporated from the stock exchanges because the stockholders lost the trust and confidence in it.
7	Regulatory actions may impact the approval of pending and new drug applications.
8	The company may need to go for a major structural change which disrupts the current running system in all aspects. As a result growth rate may decrease and the future of the company moves into the danger zone.
9	A criminal investigation may be ordered against the company which may result in prosecution.
10	Regulatory agencies may consider the products manufactured by the company are adulterated; this further leads to the seizure of the drugs.

Here is the list of top 6 penalties in the last 27 years, for the violation of Federal Laws relevant to manufacturing.

Source of the data : Twenty-Seven Years of Pharmaceutical Industry Criminal and Civil Penalties: 1991 Through 2017

1. GlaxoSmithKline

Year : 2012

Total Penalty ($ millions) : 3000

Laws violated : FCA (False Claims Act); FDCA (Food, Drug, and Cosmetic Act)

Violation : Unlawful promotion; Kickbacks; Concealing data; Overcharging govt. health programs

Products involved: Paxil; Wellbutrin; Advair; Lamictal; Zofran; Imitrex; Lotronex; Flovent; Valtrex; Avandia

2. Johnson & Johnson

Year : 2013

Total Penalty ($ millions) : 2006

Laws violated : FCA (False Claims Act); FDCA (Food, Drug, and Cosmetic Act)

Violation : Unlawful promotion; Kickbacks; Concealing data;

Products involved: Risperdal; Invega; Natrecor

3. Abbott

Year : 2012

Total Penalty ($ millions) : 1500

Laws violated : FCA (False Claims Act); FDCA (Food, Drug, and Cosmetic Act); AntiKickback Statute

Violation : Unlawful promotion; Kickbacks; Concealing data

Products involved: Depakote

4. GlaxoSmithKline

Year : 2010

Total Penalty ($ millions) : 750

Laws violated : FCA (False Claims Act); FDCA (Food, Drug, and Cosmetic Act

Violation : Poor manufacturing practices

Products involved: Kytril; Bactroban; Paxil CR; Avandame

5. Schering Plough

Year : 2002

Total Penalty ($ millions) : 500

Laws violated : FDA Current Good Manufacturing Practices

Violation : Poor manufacturing practices

Products involved: -

6. Daiichi Sankyo

Year : 2013

Total Penalty ($ millions) : 500

Laws violated : FCA (False Claims Act); FDCA (Food, Drug, and Cosmetic Act)

Violation : Poor manufacturing practices; Concealing data

Products involved:Cefaclor; Cefadroxil; Amoxicillin; Amoxicillin/Clavulanate; Sotret; Gabapentin; Ciprofloxacin )

Summary

The purpose of data integrity enforcement rules is to bring safe medicines into the market. 21 CFR belongs to the United States of America and it is applicable to those companies which are exporting and selling medicinal drugs in the USA.

Data may exist in paper format and electronic format; in some cases in hybrid form, i.e., a combination of both paper and electronic records. All records come under the scope of cGMP if they are generated as part of the manufacturing process.

All electronic records that are generated as part of predicated rules requirements, should comply with 21 CFR Part 11.

Paper records are static one and their integrity is dependent upon the person's behavioral integrity. Hence, they need a perfect verification system to rely on them for decision making.
Electronic records are dynamic one; the user can interact with the data even after the generation of the record. So, adequate system controls should be in place before using them for decision making.

Severe consequences have to be faced if a breach occurs to data integrity. It can lead to warning letters, untitled letters, import alert, consent decrees, seizures and injunctions.

The product is considered as an adulterated drug under US law if a breach in the integrity of data is observed by the FDA.

It is the immediate responsibility of the pharma companies to take steps to prevent the breaches to data on the war foot basis. It is important to realize that the consequences make the company's situation worst.

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Author Profile

Ram Kumar Reddy

Ram Kumar Reddy is the founder of Pharma Times Now. Helping Pharmacy and Chemistry students, along with the pharma employees, in learning pharmaceutical science. He has 24 years of rich experience in the Pharmaceutical industry and well versed in quality systems. He worked with Dr.Reddys and Sai Life Sciences. He lives in Hyderabad, India.