How To Prevent Data Integrity Issues In Pharma QC Lab?

Data-Integrity-in-QC

Data integrity is always a buzzing topic in the pharmaceutical industry. It creates more attention, especially when it is linked with Quality Control (QC) Laboratory. Laboratory testing data is a main source for the regulatory agencies to assess the transparency of a pharmaceutical company. The extent of quality of a product is determined based on this lab data. Hence, the regulatory agencies are focusing on the lab data at first. Unfortunately, the main ingredient of recent warning letters is a breach of data integrity in the QC Laboratory.

Why Do Regulatory Agencies Make QC Lab As Their Primary Target?

Quality Control (QC) laboratory is an important function and the heart of the pharmaceutical plant. This laboratory will verify the quality of a pharmaceutical product and establish the evidences in the form of test reports.

The degree of 'product quality' is measured through various chemical and instrumental test methods. Product releases into the market based on the certification given by the QC laboratory. If for any reason, the quality of a product is manipulated, it directly affects the patient and leads to fatal incidents.

A lot of data will be generated during the testing of a product at different stages of manufacturing. This data directly reveals whether the quality is maintained throughout the manufacturing process or not.

The progress of the manufacturing process depends on this laboratory testing data. A wrong result leads to the production of an unintended product which is not fit for the treatment of patients.

QC laboratory records the testing information in both forms: manually on paper and digitally on hard disks. Hence, the effectiveness of the controls that established for the protection of data integrity determines the level of the reliability of data.

Since the QC data is being used in the decision making of a manufacturing process, its accuracy is an essential requirement to control the quality of a product at all stages. The intentional or unintentional errors should not lead to the manufacture of adulterated drugs.

So, product's and patient's fate depends on the QC laboratory performance. The lab should never lose its hold on self-integrity while delivering the services to the manufacturing plant, even under tremendous business pressure.

The compromise in testing of a medicinal drug, puts the patients' life in risk. Due to this reason, regulatory agencies verify the QC data so deeply, to confirm the cGMP requirements.



What Are The Main Activities Of QC Laboratory?

The structure of the Quality Control laboratory is a little bit complex in its nature. Different type of activities will run simultaneously as a part of the testing process. Many things to be ensured and followed before testing a product. The quality of testing depends on the person's expertise and accuracy of the instrument used in the process.

The nature of work in the QC lab majorly relates to the analytical thinking and decision making. So the accuracy of the test result depends upon the analytical chemist's capability to handle the things accurately and his overall awareness of the testing environment. The qualities and skills required to work in QC laboratory are different from manufacturing department. There is no comparison at all.

Activities in Quality Control laboratory

Lab Activities

The QC laboratory tests all kinds of materials at all stages. Generally, all raw materials, packaging materials, in-process samples, intermediates, solvents, finished product, stability samples and R&D samples are tested and analyzed in a QC laboratory for their quality.

Simple to complex instruments are used to test the materials. Instruments such as pH meter and conductivity meter are the simple instruments. HPLC, AAS, Particle Size Analyzer, etc., are complex instruments. Only qualified analysts would be conducting the tests with the help of calibrated instruments or equipment.

Quality Control laboratory collects the sample from the production area, using a scientifically established sampling procedure for the purpose of testing. It tests the samples using a validated test method and declares the results to production department by releasing a test report which also includes the status of material, i.e., approved or rejected.

The number and types of tests to be conducted on a sample depends upon the stage, nature and objective of the testing. The laboratory conducts the tests to: identify the materials, confirm chemical and physical properties of a product, estimate impurities in a product, establish a stability period of the material.

QC lab conducts tests such as pH, conductivity, melting point, water content and bulk density, to understand the chemical properties of a product. It also performs instrumental analysis, such as HPLC, GC, X-ray diffraction and LC-MS to estimate the impurity level in a product.



What Type Of Data Is Generated In The QC Laboratory?

QC-Data

A lot of variety of data may generate in the Quality Control laboratory in the process of analytical testing. Each data has its own significance and at the same time, it is interlinked with the other data. That is the complexity of the QC department.

The accuracy of the final test result depends upon the accuracy of the other relevant data. For example, the accuracy of the pH value of a solution is dependent on the accuracy of the calibration of a pH meter. The accuracy of pH meter calibration is again dependent on the validity of standard solutions used in the calibration.

Let us see some data that is essential to generate in the QC laboratory.

A. Analyst
1. Training Record
2. Analyst Qualification Record
3. Analyst Proficiency Test Record

B. Instrument
1. Instrument Qualification/Requalification Records(DQ, IQ, OQ and PQ)
2. Instrument Calibration Records
3. Software validation records
4. Software revalidation records
5. Instrument maintenance records
6. Investigation reports of Instrument calibration failure

C. Analytical Method
1. Development report of analytical method
2. Validation report of analytical method

D. Chemicals and Test Solutions
1. Raw data of preparation of test solutions
2. Raw data of Working Standard material qualification
3. List of expiry dates of chemicals and solvents
4. List of reference standards with expiry dates
5. Raw data of standard solutions.

E. Testing
1. Batch sample inward record
2. Batch sampling record
3. Raw data of batch testing
4. Chromatograms of a product
5. Batch reserve sample record
6. Batch quality review record
7. Reconciliation of Approved/Rejected labels
8. Investigation of OOS/OOT batches
9. Investigation of incidents that occurred during the testing
10. Investigation of deviations that happened during the testing

F. Stability Study
1. Schedule of stability studies
2. Investigation reports of stability failures
3. List of expiry dates of Intermediates and finished products
4. Qualification records of stability chambers
5. Temperature and humidity sensor calibration in stability chambers
6. Temperature and humidity data of chambers
7. Reports of stability chamber failures



What Is The Difference Between GLP and GMP?

GMP-GLP

Good Manufacturing Practices (GMP) and Good Laboratory Practices (GLP) are not two different things. GLP is one of the steps of GMP Concept and an integral part of the GMP. GMP applies to the whole drug manufacturing process, i.e., from raw material procurement to delivery of the final product into the market.

The words "Manufacturing process" have a broad meaning. It includes every department in the manufacturing plant, not only the production department. GMP applies to every department. GMP assures that accurate and transparent processes are executed in all corners of the plant to produce a high-quality medicinal drug.

Many people think that GMP applies to only manufacturing activities. Manufacturing means it's not only mixing of some chemicals at multiple stages, but it also includes all work functions from all directions which makes that process possible. These work functions should have sufficient strength and capability to execute the things with accuracy from their area.

GLP applies to the laboratories that are involved in the testing of materials and at the same time these laboratories are also a natural part of manufacturing plant. The activity of testing of materials is an indivisible portion of the manufacturing process. This means the QC laboratories are part of the manufacturing process.

GLP defines some procedures which will help the laboratory in conducting accurate testing of materials. There are so many things to be maintained and ensured before proceeding for the testing of materials. GLP directs to ensure the below mentioned things to get the accurate and reliable results.

1. Qualification of analytical instruments 11. Calibration of analytical instruments.
2. Qualification of software 12. Maintenance of working/reference standards.
3. Qualification of analyst 13. The effectiveness of glassware cleaning procedure.
4. Establishment of the validity period of standard solutions 14. Maintenance proper lighting and environment.
5. Establishment of the validity period of working/reference standards 15. Product handling procedures to protect its integrity till the test results are released.
6. Proper labelling and identification of chemicals/reagents/standard and test solutions. 16. Good documentation procedures to record the original data.
7. Establishment of a suitable environment for the products to be tested, based on their stability. 17. Maintenance of all raw data.
8. Maintenance of high-quality chemicals and reagents. 18. Maintenance of log books for all equipment.
9. Validation of analytical test methods. 19. Reconciliation of Approved/Rejected labels.
10. Implementation of Safety measures in the laboratory. 20. Maintenance of critical spare parts of analytical instruments.

The GLP looks like a separate concept when you behold the view only from a laboratory perspective. But, when you enhance the range of your insight, you may clearly see its unification with GMP.



Why Do Data Integrity Issues Arise In QC Laboratory?

QC Data Issues

Before proceeding into the subject, the first thing you have to understand is the meaning of data integrity. Data integrity refers to the accuracy, legibility, contemporary, originality and attributability of a record throughout its lifecycle. A breach of data integrity means a modification of the original data either intentionally or unintentionally.

The other thing you need to focus on is the number of factors and ways that are affecting the data integrity.

The activities in the QC laboratory are dependent on both analytical chemists and instruments, which have their own limitations. Many factors (internal and external) influence their work function in different ways.

Breach of data integrity may happen in many ways. All the sources, steps and mechanisms should work perfectly in harmony to produce a test result of a product. Then only the generated data has integrity and sanctity.

Internal Factors

Internal factors are often related to the capacity of the workforce to carry out the given task with a wholistic approach. The quality of the basic traits of analytical chemist and instrument plays a major role in the execution of a given task.

The following situations may lead to the breach in data integrity:

The scope for the breach of data integrity due to the analytical chemist:
1. An unqualified/disqualified person might have been allowed to test the product.
2. Low attention/negligence of analytical chemist, in ensuring the necessary things such as the validity period of chemicals, instrument calibration and validation of test methods.
3. The inability of an analytical chemist to understand the written procedures.
4. An intentional approach to record the data without testing a product where there is no traceable mechanism.

The scope for the breach of data integrity due to the analytical instrument:
1. The unqualified/disqualified instrument might have been used to test the product.
2. The instrument operates with vulnerable software.
3. Running of the equipment with a non-validated software.
4. Undetected errors in the components of an instrument may be producing erroneous results.

External Factors

External factors are often related to business pressures and strategies. The company's work culture and aim of the business, influence the services of QC Laboratory in a significant way. The following situations may lead to the breach of data integrity.

Factors that cause a breach of data integrity :

Company's Work Culture
1. Dual management: Records would be in place as per cGMP to show the regulatory agencies. But the real management is through oral instructions.
2. QC laboratory reports to the manufacturing department, which forces it to work as per the business requirements.
3. Management treats QC Laboratory as a service function and other than that it has no importance.
4. Neither manufacturing nor quality functions own the QC laboratory as their integral part.
5. The company feels that production and delivery are the foremost things to concentrate.

Business Motto
1. Profit has the primary importance than quality.
2. Allotment of fewer resources to QC laboratory as part of budget control.
3. Compromise in the quality of laboratory chemicals and reagents as part of cost control.
4. Not investing in the tamper-proof solutions of data and retaining the tampering sources as part of business strategy.



What Are The Major Data Integrity Issues Identified By The Regulatory Agencies In QC Laboratories?

QC Audit Report

In recent years, many warning letters were issued by the regulatory agencies due to the data integrity issues.

QC laboratory is one of the major areas that hold the flag of data integrity issues.

Let us look into the concerns that led to the warning letters.

The below-listed observations are directly or indirectly connected with the data integrity issues in the QC laboratory.


1. Weighing on analytical balances
  1. Reprinting of weighing slips with back date and time.
  2. Adjustment of weights in case of water and assay testing.
  3. Insufficient calibration of analytical balances.
  4. Installation of analytical balances in an uncontrolled environment.
2. Sampling of materials
  1. Incorrect sampling procedure
  2. Repeat sampling without scientific justification
  3. Unofficial sampling for testing into compliance
  4. Unscientific sampling procedures
3. Handling of analytical instrument/equipment
  1. Insufficient equipment qualification
  2. Insufficient calibration procedures of analytical instruments
  3. Insufficient performance verification of analytical equipment
  4. Unofficial change of critical parts in analytical equipment
  5. Not recording equipment malfunctions during testing
  6. Not investigated calibration failures in full length
  7. Equipment connected with non-validated software
4. Software
  1. Software is not built with sufficient controls
  2. The software is built to record only limited parameters of batch testing
  3. Shared user account and password are in use to access the software
  4. The audit trail is not enabled in the software
  5. Software does not contain an audit trail facility
  6. Inadequate security from cyber attacks
  7. Administrator rights are provided to the QC personnel
  8. No control over the folders and data files in the Operating System
5. Analytical Chemist
  1. Insufficient training to the analytical chemists
  2. No training schedule for analytical chemists
  3. Not assessed the effectiveness of training after its completion
  4. The analytical chemist was not trained and qualified to perform the test
6. Test procedures
  1. Inadequate test procedures are used for the testing of materials
  2. Non-validated test procedures are used for the testing of materials
  3. Test procedures are difficult to understand by the analyst
  4. Test procedures are not elaborative
7. Testing
  1. Unofficial testing in another lab before proceeding for the testing in the main QC laboratory
  2. Repeated testing until getting the final passed results
  3. Testing with anonymous batch numbers instead of the original one
  4. Only passed results are reported ignoring failed results
  5. Failed results are not investigated prior to batch release
  6. Test record generation using a passed batch material
  7. False integration of peaks in a chromatogram to pass the batch
  8. Not following the contemporaneous recording of the data
  9. Batch release before releasing of QC test data
  10. Use of non validated spreadsheets (MS Excel) for the calculations
8. Electronic Records
  1. Deletion of raw data files which contain failed results of a batch
  2. Multiple reprocessing of chromatograms in HPLC/GC analysis
  3. Intentional modification of the data to release the batch
  4. A partial backup of electronic data
  5. Backup procedures are not validated
  6. Data Backup policy is not developed by the company
  7. Unsecured electronic signatures
9. Paper Records
  1. Fabrication of employee training records
  2. Falsification of data to meet the requirements
  3. Fabrication of test reports to release the batch
  4. Replacement of original records with newly created data during the regulatory inspection
10. Documentation
  1. Deviations are not documented and investigated
  2. Laboratory incidents are not documented and investigated
  3. Software and firmware errors are not documented and investigated
  4. Multiple sampling is not documented and investigated
  5. Department self-inspection observations are not documented completely
  6. Submission of falsified data to the authorities to get approvals

All the above-mentioned observations are the root causes of the data integrity issues and warning letters. If you don't rectify these unwanted things today, it is for sure that you will receive a warning letter tomorrow at any moment.

Refer the below websites to see Warning Letters:

US FDA Warning Letters

EU - GMP Non Compliance Reports



What Strategies Have To Be Implemented To Avoid The Data Integrity Issues In QC Laboratories?

Data Control Strategy

In the case of QC laboratory, one must be very careful about the things happening round the clock. Even a small mistake, sometimes it may not be visible, may lead to a big error in the analysis.

This is why the people working in the laboratories should have a skill which is called "keen observation".

There are numerous things which can influence the final result. They may have a direct or indirect relationship. It is not that much easy to identify the gaps that leading to the errors in analytical testing.

Also, it is very difficult to scrutinize each and every single step on a daily basis. Hence, a broad, comprehensive approach, which can control the whole system, is required to move the things in a compliant way. Follow the given below strategies.

1 Develop an open culture in the QC lab.
2 Amend the Organogram to change the reporting system of the QC laboratory. QC Laboratories should report to the Corporate QC and Corporate QC to the CEO. Then only things will move in a compliant way.
3 Don't allow business pressure on the QC Lab Head and staff.
4 Form a dedicated IT team for QC at the corporate level to handle software, firmware and backup of electronic data.
5 Form a dedicated investigation team in the QC lab to investigate, lab incidents, deviations, calibration failures and OOS.
6 Implement an effective training program for all QC employees.
7 Establish a scientific qualification program for analyst qualification.
8 Establish date and time controls on all computerized systems.
9 Validate all your MS Excel spreadsheets which are used for the calculations.
10 Must validate the software after the installation on computer hard disk. Only getting a validation certificate from the software designer, won't provide any value in a regulatory point of view. You must test the software in the actual environment for its accuracy and reproducibility.
11 Eliminate all software which doesn't have adequate facilities such as individual user login accounts, controls on deletion and modification of data and audit trail facility.
12 Explore the ways to eliminate manual recording of test results and use instruments equipped with software to the possible extent in place of manual testing.
13 Establish the second competent person review wherever the manual recording is unavoidable.
14 Form a dedicated team for calibration of analytical instruments and performance verification of analytical equipment.
15 Establish standard procedures for sampling and resampling of materials.
16 Make a schedule for the self-inspection of the department and strictly implement it. Allow the auditor to inspect the lab as the FDA auditor does.
17 Disable recycle bin in all computers and restrict the access of computers with an individual user login and password.
18 Do not give permission, to access or create folders, to the lab personnel in the computers which connected to analytical instruments or equipment.
19 Connect all standalone instruments to a local server and enable instant backup of the server.
20 All blank forms should be controlled by the QA and it is the responsibility of QA to prevent the availability of unauthorized copy in QC.
21 Define a policy for the integration of peaks in chromatography.
22 Establish a system of weekly reporting, on QC data integrity issues, to the Company CEO/Chairman.
23 Immediately conduct a risk identification program to identify the hidden risk in existing data generation and storing systems.
24 Design risk elimination or control programs for all analytical processes in the QC Lab.
25 Arrange all the necessary resources (chemicals and glassware) to the analytical chemist to perform a test.
26 Don't allow the production personnel to sit in front of the analyst creating pressure for the batch release. Give sufficient time to the analyst to perform the test in the right way as per the written procedure.
27 Design a thorough inspection system to identify the data integrity issues the moment they occurred.
28 Without a proper investigation of data integrity issue and implementation of the CAPA, the affected batches should not release for further purposes.
29 Immediately notify the customer/regulated agency and recall the material if a data integrity issue is identified in a particular batch testing, after its release into the market or to a customer.
30 All the software installations, facility changes, qualification and requalification, revision of 'blank form' format and revision of a test method should happen through the Change Control (CC) system.
31 Remove the fear of invalid OOS from the staff's mind. Invalid OOSs are quite natural and bound to come due to manual errors, system errors and procedural errors.
32 Protect the analytical chemist from the external pressures which influence him to invalid the real OOS in wrong ways. Don't give scope to anybody to take the advantage of invalidating an OOS by attributing it to a lab error.
33 Estimate the risk posed to the electronic and paper records and develop suitable mechanisms to eliminate or avoid it.

This wholistic approach definitely prevents many issues related to the data integrity in the QC laboratory. The only thing required is a commitment from the staff and management. In my opinion, the commitment of senior management, to give liberty to the QC lab, plays a major role in the whole exercise.



What Is The Role Of Company's Senior Management, In Protecting The Liberty And Integrity Of The QC Laboratory?

Management Care

Senior management has to ensure the elimination of the following misconceptions in the company. This reveals the culture and the level of quality consciousness prevailed in the company.

1. One sad thing is that often the QC laboratory is treated as a service department and the manufacturing division as a core function. This is because the QC laboratory will not produce any product and investment into it is non-returnable.

This type of unscientific discrimination and narrow division makes things worse and affecting the laboratories' performance in many ways. In fact, no department is superior to the other in a manufacturing plant.

Each department has its own special characteristics and functionalities to deliver the things. Sweeper to plant head, everyone has his own role to play, which is unique to them.

The selling price of a product includes the cost of every department and every individual, not only any one particular department's cost.

2. QC Laboratory is a burden to the business and consumes much time in the testing of the materials.

Every work in the world has its own length of time to show its output. Similarly, the laboratory test also contains some duration of time to produce a result. No one can reduce the testing time beyond its inherent duration unless otherwise he/she skips some of the steps to be followed.

If you want accurate test results, give sufficient time to the analytical chemist to work on it. QC Laboratory is not a burden. In fact, it is a saviour of the company. It becomes the prime source of pride for the company if utilized in an ethical way.

For an analogy, if you consider a product as a human body, then the QC analytical data become its blood. If your blood is good, then your body also remains in good status.

Even a single particle in the bloodstream collapses the whole body. One warning letter closes the entire business that was built with years of hard work.

Senior management has to focus on the following situations in the company.

1. Don't allow business pressure on the QC Lab Head and staff.

It's quite natural that business commitments create a lot of pressure on the heads of marketing and production teams. They wish their product should release into the market before the entry of their business rival's product.

During this phase, they start to feel the QC testing time as a delayer of the business. They don't consider QC testing time as a part of the manufacturing process. As a result, laboratory personnel receive tremendous pressure to release the batch. The Head of QC laboratory is the first victim of this process.

If the business pressure is at a high level, laboratory personnel start to explore the shortcuts to release the batch, skipping all compliance requirements. This is a self-created dangerous situation which later on leads to unrecoverable permanent damage.

2. Don't allow temptations such as salary increments and promotions for facilitating the business in wrong ways.

This embarrassing situation is visible in the majority of the companies. The growth of QC laboratory personnel is dependent on the mere opinions of the manufacturing and marketing teams.

The fate of the QC laboratory personnel is in the hands of manufacturing and marketing divisions. They influence the growth of QC staff in the form of a member of the committee, which formed to decide the promotions and increments of the employees.

The performance of laboratory personnel should be measured based on the QC related testing activities and adherence to the compliance, but not based on the number of batches released in support of the business. The accuracy and reliability of the test data should be the actual criteria for the performance measurement.

The nature of QC Lab work is entirely different from the work executed in the manufacturing and marketing divisions. People working in those divisions can never ever perceive and understand the difficulties and complexities involved in performing a test.

People are using this opportunity as an indirect blackmailing source. That is why the majority of the analytical chemists are continually under pressure and committing to unwanted noncompliance activities.

It is up to the management's discretion how to run the business with a non-remarkable quality and ethics. It does not matter whether the companies agree or disagree with the above points, but they are the facts and the real prevailed situations in the industry. This is the true feedback.

The business will reach the new heights when the company's management starts the correction of existing pitfalls. Rational thinking on the current requirements and working function always puts the company in the right direction. Every initiation that has been taken by the company, to protect the QC Laboratory's integrity, ultimately leads to the uninterrupted business of high-quality products with ethics.



Summary

QC Laboratory is treated as a heart of business in any pharmaceutical company on the globe. All regulatory agencies' focus automatically falls on the QC laboratory because it is, testing and certifying the quality of the medicinal products.

All equipment, software, testing processes and data management should meet the regulatory requirements set forth in the law.

The skill of the analytical chemist, the capability of analytical instrument and the level of controls on breaching of data integrity, determines the ultimate quality of testing and reliability of test results.

Business pressure is significantly affecting the activities in the laboratory. It is often caused the non-compliance issues in the lab and finally leading to the punishments by the regulatory authorities.

Sufficient resources, continuous effort to increase compliance culture, liberty to QC Lab to work as per the procedures, and risk assessment of existing data generation systems are the key areas to focus on immediately to protect the integrity of laboratory data.

The intensity of management's wish, ambition, and commitment to the compliance culture is the game-changing factor in ethical business.

QC Laboratory is a great weapon which can protect the companies from the production of adulterated drugs and regulatory impacts. If it is misused, the entire business will collapse.



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Author Profile

rama-kumar-reddy-pharma-times-now

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.

21 comments:

  1. I adore the article. It is very usuful and intereseting

    ReplyDelete
  2. Very good information helpful to all

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  3. Very good article, thanks for the information.

    ReplyDelete
  4. Interesting article. request to create as APp mode

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  5. Good article benifecial for all pharma company and employs

    ReplyDelete
  6. Very nice artical for all pharma member's

    ReplyDelete
  7. Hey Ram Kumar,

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    I noticed you linked to ALCOA article.


    https://www.ympronta.it/r/tP5

    https://www.ympronta.it/en/blog/our-blog-1/post/data-integrity-in-pharmaceutical-industry-2


    if you find it valuable and share it, it would make my day.

    Regards!
    Igor

    ReplyDelete