Star Spangled Banner – Best Performances

I love to hear new versions of our national Anthem…It gives me chills. Not everyone can pull it off and these are my favorites….

My Favorite Female artists…Unique voice…

O’er the land of the free and the home of the brave!

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My Favorites Country Songs – Part I

This list is long….Part II in some no distant future..Enjoy!

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What Goes Around…Comes Around

In and Out of Love – Armin van Buuren feat. Sharon den Adel

Fine Without You -Armin van Buuren feat. Jennifer Rene

Tiesto – Love Comes Again

 

Ik ben met veel mensen geweest en op het einde realiseer je dat ‘te zijn’ alleen maar met één persoon kan gebeuren. Kerst, .. zomers, ontbijt
Ik doe het op mijn manier!

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Yvonne Koelemeijer

Read All About It

Emeli Sandé – Read All About It

systemchange_noclimatechange

 

You’ve got the words to change a nation
But you’re biting your tongue
You’ve spent a life time stuck in silence
Afraid you’ll say something wrong
If no one ever hears it how we gonna learn your song?
So come on, come on
Come on, come on
You’ve got a heart as loud as lightning
So why let your voice be tamed?
Maybe we’re a little different
There’s no need to be ashamed
You’ve got the light to fight the shadows
So stop hiding it away
Come on, come on
I wanna sing, I wanna shout
I wanna scream ’til the words dry out
So put it in all of the papers,
I’m not afraid
They can read all about it
Read all about it, oh
Oh oh oh
Oh oh oh
Oh oh oh
Oh oh oh
Oh oh oh
Oh oh oh
At night we’re waking up the neighbors
While we sing away the blues
Making sure that we’re remembered, yeah
‘Cause we all matter too
If the truth has been forbidden
Then we’re breaking all the rules
So come on, come on
Come on, come on,
Let’s get the TV and the radio
To play our tune again
It’s ’bout time we got some airplay of our version of events
There’s no need to be afraid
I will sing with you my friend
Come on, come on
I wanna sing, I wanna shout
I wanna scream ’til the words dry out
So put it in all of the papers,
I’m not afraid
They can read all about it
Read all about it, oh
Oh oh oh
Oh oh oh
Oh oh oh
Oh oh oh
Oh oh oh
Oh oh oh
Yeah, we’re all wonderful, wonderful people
So when did we all get so fearful?
Now we’re finally finding our voices
So take a chance, come help me sing this
Yeah, we’re all wonderful, wonderful people
So when did we all get so fearful?
And now we’re finally finding our voices
Just take a chance, come help me sing this
I wanna sing, I wanna shout
I wanna scream ’til the words dry out
So put it in all of the papers,
I’m not afraid
They can read all about it
Read all about it, oh
Oh oh oh
Oh oh oh
Oh oh oh
Oh oh oh
Oh oh oh
Oh oh oh
I wanna sing, I wanna shout
I wanna scream ’til the words dry out
So put it in all of the papers,
I’m not afraid
They can read all about it
Read all about it, oh

 

System Change
System Change

 

 

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Say Something

A Great Big World, Christina Aguilera

Say Something

 

 

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Understanding Audit Trail Requirements in Electronic GxP Systems

Computerized systems are used throughout the life sciences industry to support various regulated activities, which in turn generate many types of electronic records.  These electronic records must be maintained according to regulatory requirements contained within FDA’s 21 CFR Part 11 for US jurisdictions and Eudralex Volume 4 Annex 11 for EU jurisdictions.  Therefore, we must ensure the GxP system which maintains the electronic record(s) is capable of meeting these regulatory requirements.

What to look for in Audit Trail?

  • Is the audit trail activated? SOP?
  • Record of reviews? (most companies trust the electronic systems audit trail and generates electronic paper version of it without a full review)
  • How to prevent or detect any deletion or modification
    of audit trail data? Training of staff?
  • Filter of audit trail

Can you prove data manipulation did not occur?

Persons must still comply with all applicable predicate rule requirements related to documentation of, for example, date (e.g. 58.130(e)), time, or sequencing of events, as well as any requirements for ensuring that changes to records do not obscure previous entries.

Consideration should be given, based on a risk assessment, to building into the system the creation of a record of all GMP-relevant changes and deletions (a system generated “audit trail”).

Audit trail content:

Audit trail content and reason it is required:
Identification of the User making the entry This is needed to ensure traceability.  This could be a user’s unique ID, however there should be a way of correlating this ID to the person.
Date and Time Stamp This is a critical element in documenting a sequence of events and vital to establishing an electronic record’s trustworthiness and reliability.  It can also be effective deterrent to records falsification.
Link to Record This is needed to ensure traceability.  This could be the record’s unique ID.
Original Value  

This is needed in order to be able to have a complete history and to be able reconstruct the sequence of events

New Value
Reason for Change This is only required if stipulated by the regulations pertaining to the audit trailed record.  (See below)

FDA / Regulators findings and complaints during Inspection of Audit Trail Data:

  • Audit User sometimes is hard to describe (e.g. user123 instead use full names of each user IDs thus requirement additional mapping)
  • Field IDs or Variables names are used instead of SAS labels or Field Labels (map field names with respective field text (e.g.  AETERM displayed instead use Reported Term for the Adverse Event)
  • Default values should be easily explained or meaningful (see annotated CRF)
  • Limited access to audit trail files (many systems with different reporting tools or extraction tool. Data is not fully integrated. Too many files and cannot be easily integrated).
  • No audit trail review process. Be prepared to update SOPs or current working practices to add review time of audit trails. It is expected that at least, every 90 days, qualified staff performed a review of the audit trail for their trials. Proper documentation, filing and signature should be in place.
  • Avoid using Excel or CSV files. Auditors are now asking for SAS datasets of the audit trails. Auditors are getting trained to generate their own output based on pre-defined set of parameters to allow auditors to summarize data and produce graphs.
  • Formatting issues when exporting into Excel, for example.  Numbers and dates fields change it to text fields.
Audit Trail Review

What data must be “audit trailed”?

When it comes to determining on which data the audit trail must be applied, the regulatory agencies (i.e. FDA and EMA) recommend following a risk based approach.

Following a “risk based approach”

In 2003, the FDA issued recommendations for compliance with 21 CFR Part 11 in the “Guidance for Industry – Part 11, Electronic Records; Electronic Signatures — Scope and Application” (see reference: Ref. [04]).  This guidance narrowed the scope of 21 CFR Part 11 and identified portions of the regulations where the agency would apply enforcement discretion, including audit trails. The agency recommends considering the following when deciding whether to apply audit trails:

  • Need to comply with predicate rule requirements
  • Justified and documented risk assessment to determine the potential effect on product quality
  • product safety
  • record integrity

With respect to predicate rule requirements, the agency states, “Persons must still comply with all applicable predicate rule requirements related to documentation of, for example, date (e.g., § 58.130(e)), time, or sequencing of events, as well as any requirements for ensuring that changes to records do not obscure previous entries.”  In the docket concerning the 21 CFR Part 11 Final Rule, the FDA states, “in general, the kinds of operator actions that need to be covered by an audit trail are those important enough to memorialize in the electronic record itself.” These are actions which would typically be recorded in corresponding paper records according to existing recordkeeping requirements.

The European regulatory agency also recommends following a risk based approach.  The Eudralex Annex 11 regulations state, “consideration should be given, based on a risk assessment, to building into the system the creation of a record of all GMP-relevant changes and deletions (a system generated “audit trail”).”

MHRA Audit

When does the Audit Trail begin?

The question of when to begin capturing audit trail information comes up quite often, as audit trail initiation requirements differ for data and document records.

For data records:

If the data is recorded directly to electronic storage by a person, the audit trail begins the instant the data hits the durable media.  It should be noted, that the audit trail does not need to capture every keystroke that is made before the data is committed to permanent storage. This can be illustrated in the following example involving a system that manages information related to the manufacturing of active pharmaceutical ingredients.  If during the process, an operator makes an error while typing the lot number of an ingredient, the audit trail does not need record every time the operator may have pressed the backspace key or the subsequent keystrokes to correct the typing error prior to pressing the ‘‘return key’’ (where pressing the return key would cause the information to be saved to a disk file).  However, any subsequent ‘‘saved’’ corrections made after the data is committed to permanent storage, must be part of the audit trail.

For document records:

If the document is subject to review and approval, the audit trail begins upon approval and issuing the document.  A document record undergoing routine modifications, must be version controlled and be managed via a controlled change process. However, the interim changes which are performed in a controlled manner, i.e. during drafting or review comments collection do not need to be audit trailed.  Once the new version of a document record is issued, it will supersede all previous versions.

Questions from Auditors: Got Answers?

When was data locked? Can you find this information easily on your audit trail files?

When was the database/system released for the trial? Again, how easily can you run a query and find this information?

When did data entry by investigator (site personnel) commence?

When was access given to site staff?

Source:

Part of this article was taking, with permission, from Montrium – Understanding Audit Trail Requirements in Electronic GXP Systems

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How to Avoid Electronic Data Integrity Issues: 7 Techniques for your Next Validation Project

The idea of this article was taking (with permission from the original authors) from Montrium:  how-to-avoid-electronic-data-integrity-issues-7-techniques-for-your-next-validation-project

Regulatory agencies around the globe are causing life science companies to be increasingly concerned with data integrity.  This comes with no surprise given that Guidance Documents for Data Integrity have been published by the MHRAFDA (draft), and WHO (draft).  In fact, the recent rise in awareness of the topic has been so tremendous that, less than two years after the original publication, the MHRA released a new draft of its guidance whose scope has been broadened from GMP to all GxP data.

Is data integrity an issue of good documentation practices? You can read GCP information about this topic here.

Good Documentation Practices for SAS / EDC Developers

Are you practising GCP?

In computerised systems, failures in data integrity management can arise from poor or complete lack of system controls.  Human error or lack of awareness may also cause data integrity issues.  Deficiencies in data integrity management are crucial because they may lead to issues with product quality and/or patient safety and, ultimately may manifest themselves through patient injury or even death.

I recently was at the vendor qualification tool that uses a hand held device to read data while the physician or expert manually put pressure on someone’s body parts (e..g. pain related). I was not impressed. Even though it seems like a nice device with its own software, the entire process was manual and therefore, questionable data integrity. The measurement seems to be all over the place and you would need the right personnel at the clinical site to perform a more accurate reading since again, it was all manual and dependent of someone else used of the device.

I also questioned the calibration of this device. The sale’s person answer ? “Well, it is reading 0 and therefore, it is calibrated.”….Really? You mean to tell me you have no way of proving when you perform calibration? Where is the paper trail proving your device is accurate? You mean to tell me I have to truth your words? Or your device’s screen that reads ‘0’? Well, I have news for you. Tell that to the regulators when they audit the trial.

What is Data Integrity?

Data can be defined as any original and true copy of paper or electronic records.  In the broadest sense, data integrity refers to the extent to which data are complete, consistent and accurate.

To have integrity and to meet regulatory expectations, data must at least meet the ALCOA criteria. Data that is ALCOA-plus is even better.

Alcoa

 

What is a Computerised System?

computerised system is not only the set of hardware and software, but also includes the people and documentation (including user guides and operating procedures) that are used to accomplish a set of specific functions.  It is a regulatory expectation that computer hardware and software are qualified, while the complete computerised system is validated to demonstrate that it is fit for its intended use.

How can you demonstrate Electronic Data Integrity through Validation?

Here are some techniques to assist you in ensuring the reliability of GxP data generated and maintained in computerised systems.

Specifications

What to do

Why you should do this

Outline your expectations for data integrity within a requirements specification.

For example:

  • Define requirements for the data review processes.
  • Define requirements for data retention (retention period and data format).
Validation is meant to demonstrate a system’s fitness for intended use.  If you define requirements for data integrity, you will be more inclined to verify that both system and procedural controls for data integrity are in place.
Verify that the system has adequate technical controls to prevent unauthorised changes to the configuration settings.

For example:

  • Define the system configuration parameter within a configuration specification.
  • Verify that the system configuration is “locked” to end-users.  Only authorized administrators should have access to the areas of the system where configuration changes can be made.
The inspection agencies expect you to be able to reconstruct any of the activities resulting in the generation of a given raw data set.  A static system configuration is key to being able to do this.

 

Verification of Procedural Controls

What to do

Why you should do this

Confirm that procedures are in place to oversee the creation of user accounts.

For example:

  • Confirm that user accounts are uniquely tied to specific individuals.
  • Confirm that generic system administrator accounts have been disabled.
  • Confirm that user accounts can be disabled.
Shared logins or generic user accounts should not be used since these would render data non-attributable to individuals.

System administrator privileges (allowing activities such as data deletion or system configuration changes) should be assigned to unique named accounts.  Individuals with administrator access should log in under his named account that allows audit trails to be attributed to that specific individual.

Confirm that procedures are in place to oversee user access management.

For example:

  • Verify that a security matrix is maintained, listing the individuals authorized to access the system and with what privileges.
A security matrix is a visual tool for reviewing and evaluating whether appropriate permissions are assigned to an individual. The risk of tampering with data is reduced if users are restricted to areas of the system that solely allow them to perform their job functions.
Confirm that procedures are in place to oversee training.

For example:

  • Ensure that only qualified users are granted access to the system.
People make up the part of the system that is most prone to error (intentional or not).  Untrained or unqualified users may use the system incorrectly, leading to the generation of inaccurate data or even rendering the system inoperable.

Procedures can be implemented to instruct people on the correct usage of the system.  If followed, procedures can minimize data integrity issues caused by human error. Individuals should also be sensitized to the consequences and potential harm that could arise from data integrity issues resulting from system misuse.

Logical security procedures may outline controls (such as password policies) and codes of conduct (such as prohibition of password sharing) that contribute to maintaining data integrity.

 

Testing of Technical Controls

What to do

Why you should do this

Verify calculations performed on GxP data.

For example:

  • Devise a test scenario where input data is manipulated and double-check that the calculated output is exact.
When calculations are part of the system’s intended use, they must be verified to ensure that they produce accurate results.
Verify the system is capable of generating audit trails for GxP records.

For example:

  • Devise a test scenario where data is created, modified, and deleted.  Verify each action is captured in a computer-generated audit trail.
  • Verify the audit trail includes the identity of the user performing the action on the record
  • Verify the audit trail includes a time stamp
  • Verify the system time zone settings and synchronisation.
With the intent of minimizing the falsification of data, GxP record-keeping practices prevent data from being lost or obscured.  Audit trails capture who, when and why a record was created, modified or deleted.  The record’s chronology allows for reconstruction of the course of events related to the record.

The content of the audit trails ensures that data is always attributable and contemporaneous.

For data and the corresponding audit trails to be contemporaneous, system time settings must be accurate.

 

 

 

Who can delete data?

Adequately validated and have sufficient controls to
prevent unauthorized access or changes to data.

Implement a data integrity lifecycle concept:

  • Activate audit trail and its backup
  • Backup and archiving processes
  • Disaster recovery plan
  • Verification of restoration of raw data
  • Security, user access and role privileges (Admin)

Warning Signs – Red Flags

  • Design and configuration of systems are poor
  • Data review limited to printed records – no review
    of e-source data
  • System administrators during QC, can delete data (no proper documentation)
  • Shared Identity/Passwords
  • Lack of culture of quality
  • Poor documentation practices
  • Old computerized systems not complying with part 11 or Annex 11
  • Lack of audit trail and data reviews
  • Is QA oversight lacking? Symptom of weak QMS?
I love being audited

 

 

 

 

 

 

Perform Self Audits

  • Focus on raw data handling & data review/verification
  • Consider external support to avoid bias
  • Verify the expected sequence of activities: dates,
    times, quantities, identifiers (such as batch,
    sample or equipment numbers) and signatures
  • Constantly double check and cross reference
  • Verify signatures against a master signature list
  • Check source of materials received
  • Review batch record for inconsistencies
  • Interview staff not the managers

FDA 483 observations

“…over-writing electronic raw data…..”

“…OOS not investigated as required by SOP….”

“….records are not completed contemporaneously”

“… back-dating….”

“… fabricating data…”

“…. No saving electronic or hard copy data…”

“…results failing specifications are retested until
acceptable results are obtained….”

  • No traceability of reported data to source documents

Conclusion:

Even though we try to comply with regulations (regulatory expectations from different agencies e.g. EMA, MHRA, FDA, etc), data integrity is not always easy to detect. It is important the staff working in a regulated environment be properly trained and continuous refresher provided through their career (awareness training of new regulations and updates to regulations).

Companies should also integrate a self-audit program and develop a strong quality culture by implementing lesson learned from audits.

Sources:

You can read more about data integrity findings by searching the followng topics:

MHRA GMP Data Integrity Definitions & Guidance for the Industry,
MHRA DI blogs: org behaviour, ALCOA principles
FDA Warning Letters and Import Alerts
EUDRA GMDP database noncompliance

The Mind-Numbing Way FDA Uncovers Data
Integrity Laps”, Gold Sheet, 30 January 2015

Data Integrity Pitfalls – Expectations and Experiences

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Tribute to Evanescence (Music)

T E M P O Q U E N Ã O VO L T A A T R Á S

 

Evanescence @ Greek Theatre  15. Oktober 2017, 19:00
Evanescence @ Ryman Auditorium 25. Oktober 2017,  19:00

See you soon…

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Remembering the Old Good Days (Music)

T E M P O Q U E N Ã O VO L T A A T R Á S

Edward Maya & Vika Jigulina – Stereo Love (Official Music Video)

When you gonna stop breaking my heart
I don’t wanna be another one
Paying for the things I never done

Don’t let go
Don’t let go
To my love

Can I get to your soul
Can you get to my thoughts
Can you promise we won’t let go
All the things that I need
All the things that you need
We can make it feel so real

Cause you can’t deny
You’ve blown my mind
When I touch your body
I feel I’m losing control

Cause you can’t deny
You’ve blown my mind
When I see you baby
I just don’t wanna let go

When you gonna stop breaking my heart
I don’t wanna be another one
Paying for the things I never done

Don’t let go
Don’t let go
To my love

I hate to see you cry
Your smile is a beautiful lie
I hate to see you cry
My love is dying inside

I hate to see you cry
Your smile is a beautiful lie
I hate to see you cry
My love is dying inside

I can fix all those lies
Oh baby, baby I run, but I’m running to you
You won’t see me cry, I’m hiding inside
My heart is in pain, but I’m smiling for you
Oh baby I’ll try to make the things right
I need more than air when I’m not with you
Please don’t ask me why, just kiss me this time
My only dream is about you and I

Can I get to your soul
Can you get to my thoughts
Can you promise we won’t let go
All the things that I need
All the things that you need
We can make it feel so real

Cause you can’t deny
You’ve blown my mind
When I touch your body
I feel I’m losing control

Cause you can’t deny
You’ve blown my mind
When I see you baby
I just don’t wanna let go

When you gonna stop breaking my heart
I don’t wanna be another one
Paying for the things I never done

Don’t let go
Don’t let go
To my love

I hate to see you cry
Your smile is a beautiful lie
I hate to see you cry
My love is dying inside

I can fix all those lies
Oh baby, baby I run, but I’m running to you
You won’t see me cry, I’m hiding inside
My heart is in pain, but I’m smiling for you
Oh baby I’ll try to make the things right
I need more than air when I’m not with you
Please don’t ask me why, just kiss me this time
My only dream is about you and I

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ICH is coming to Town – European Medicines Agency (EMA)

The International Conference on Harmonization (ICH)  is involved in promoting public health, improve efficiency of new drug development and registration process among other objectives. In order to accomplish this, ICH has developed and implemented harmonized guidelines and standards, also known as ICH6.

ICH Steps

Over 50 guidelines on technical requirements on:
Quality, Safety and Efficacy
Efficacy – 14 topics/17 guidelines
Safety – 8 topics/16 guidelines
Quality – 9 topics/23 guidelines

  • Maintenance of ICH Controlled Terminology Lists
  • Medical dictionary for adverse event reporting and coding
    of clinical trial data (MedDRA)
  • Electronic Standards for the Transfer of Regulatory
    Information
  • Common Technical Document (CTD & eCTD)

The European Medicines Agency (EMA) is a decentralised body of the EU. EMA is responsible for centralised procedure and co-ordination of EU network + plays a role in stimulating innovation and research in the pharmaceutical sector.

EMA is not an FDA for Europe

EMA responsibility does not include:

  • Evaluation of all medicines in the EU
  • Research/development of medicines
  • Clinical trial approval
  • Medical devices
  • EU healthcare policies
EMA Regulatory Process

 

 

Conclusion: ICH-GCP guidelines brought forth public awareness that there was a need to control and regulate clinical trials dealing with drugs and human subjects.

ICH main goal is to provide a unified standard for the European Union (EU), Japan and the United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions.

Source:

Guidelines on good clinical practice (European Community and within the ICH regions)  – https://ec.europa.eu/

Presentation – ICH and EU regulatory – www.ema.europa.eu

 

Recommended Posts:

https://edcdeveloper.wordpress.com/2015/05/11/are-you-practicing-gcp/

https://edcdeveloper.wordpress.com/2011/11/17/21-cfr-part-11-cheat-sheet-for-the-edc-developer/

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