2016 annual conference stream b session 4: glp qa clinic ... · 2016 annual conference stream b...
TRANSCRIPT
2016 Annual Conference Stream B Session 4: GLP QA Clinic
Roger Chapman
Outline
• Deviations• Definitions
• Responsibilities
• Examples
• Frustrations
• CAPA requirements and expectations• GxP Regulatory references
• Adding value• Tracking and trending
Definitions
• OECD GLP:• “(GLP) is a Quality System…”
• US FDA:• “FDA proposes to amend the GLP
regulations to require the use of a complete quality system approach”
• OECD GLP:• “Study plan deviation means an
unintended departure from the study plan after the study initiation date.”
• OECD SD Consensus document:• “…a deviation is an unintended
change which occurs during the execution of the study…”
Responsibilities – Study Director (/PI)
• “…assess and document the impact of any deviations from the study plan on the quality and integrity of the study, and take appropriate corrective action if necessary…”
• “…acknowledge deviations from Standard Operating Procedures during the conduct of the study…”
• “…should be acknowledged, described, explained and dated in a timely fashion by the Study Director and/or Principal Investigator(s) and maintained with the study raw data. The Study Director should approve any corrective action taken.”
• “…should report (and discuss where necessary) these deviations in the final report…”
[OECD GLP Consensus doc #8: SDs][OECD GLP]
Responsibilities – more SD (/PI)
• “…The study director, test facility management, quality assurance and, if appropriate, the sponsor should be informed about incidents requiring remedial action. The study director is responsible for defining the criticality of incidents and for assessing the impact on the study. The root cause of an incident requiring remedial action should be identified and should form the basis of corrective and preventive actions...”
[OECD GLP Advisory #17: Computing]
Quality Assurance
• “Determine that no deviations from approved protocols or SOPs were made without proper authorization and documentation.
• For multisite studies, the lead QAU is responsible for identifying all deviations that occur across the entire study, including deviations identified by all other QAUs participating in the study…”[US FDA GLP 21CFR58.35 (b)(8, proposed)]
[21CFR58.35 (b)(5)]
Common examples of Deviations
• Temperatures outside limits • Dose/Application rates outside limits
Frustrations
• The better we get at monitoring temperatures, and the more sophisticated kit we use, the more deviations we see• Most excursions are transient
• Only rarely are temp fluctuations considered to have had any impact – e.g. a total loss of samples or compromised test systems
• Dose/Application rate deviations range from the significant to the banal• From study-stopping errors to
everyday variations hauled into the spotlight because of unrealistic expectations
• Dosing/Application excursions often come about because of arbitrary study plan criteria• I mean… how realistic is ±5% for a
pedestrian boom sprayer application in potatoes??
Trying… ….very trying!
• A myriad of caveats and exception criteria have been invented to minimise temperature deviations• Excursion durations
• Excursion magnitudes
• Mean kinetic temperatures…
Making use of your deviations
• Does your organisation just beat up on deviations?• Any chance they may be hidden
underground?
• Do you zealously subject every single one to full-blown root cause analysis and CAPA?
• Somewhere in between?
“Without deviation from
the norm, progress is not
possible.”Frank Zappa
What GLP says about CAPA
• Zero• Zilch
• Zip• Nada
• Nothing
• …SOPs must include procedures for correcting reported problems and, as necessary, for modification of relevant SOPs to prevent a recurrence of any problems…
[US FDA 21CFR58.81(b)(21), proposed]
[OECD]
CAPA requirements in GCP & GMP
• “When significant noncompliance is discovered, the sponsor should perform a root cause analysis and implement appropriate corrective and preventive actions”
• “Appropriate corrective actions and/or preventative actions (CAPAs) should be identified and taken in response to investigations (of deviations, suspected product defects and other problems).• The effectiveness of such actions
should be monitored and assessed…• Where human error is suspected or
identified as the cause, this should be justified having taken care to ensure that process, procedural or system based errors or problems have not been overlooked”
[ICH E6 Addendum]
[EU GMP Vol 4 Chapter 1]
How’s your CAPA Programme?
• Is it a process, turned on and off at will?
• Or is it a continuous programme, with routine review and oversight?
• Do you have trained practitioners?
• Is it so complicated everyone ducks? Or never gets to the end of the process?
• Is ‘Human error’ used too often as a root cause??
Where do you set your entry level for CAPA under GLP? According to severity criteria? Recurrent issues? Everything??
Writing Deviations
• Most GLP facilities have a simple Word template to standardise the format of deviations• A description of the event and the
likely impact on the study are generally free-text entries
• Sometimes, but by no means always, there is also an indication of some action to prevent recurrence
• How many of us analyse, categorise and trend our deviations??
Collating deviations
• “I often say that when you can measure what you are speaking about, and express it in numbers, you know something about it; but when you cannot measure it, when you cannot express it in numbers, your knowledge is of a meagre and unsatisfactory kind; it may be the beginning of knowledge, but you have scarcely, in your thoughts, advanced to the stage of science, whatever the matter may be.”
• Most of us already have a list, spreadsheet or database of CAPAs, but how many of us can say the same of deviations??• In small organisations, there may be a
good mental overview already (probably in QA)
• But in larger facilities, with 100s of studies…???• Doesn't that seem like a lot of extra work?
[Lord Kelvin]
Analysis
• What happened?• Which part of which SOP or study
plan wasn’t followed?• What was the real impact?
• When?• Date and time etc
• Where?
• Who?
• How was the issue resolved?• Was the solution effective and
enduring?
• Why did this happen?• May need some investigation and
root cause analysis
• Has this happened before?• Where?• When?• Who• Why?• etc
Collation
• At the very least, take a objective hard look at all the deviations in each study when you audit the draft report• Has the same type of event
recurred?
• Is there any cumulative impact?
• Has the SD made an appropriate, joined-up, assessment?
• More widely, are any groups of deviations across the business worthy of the full CAPA treatment?
• Whilst we’re on the topic… do any of your audit findings constitute ‘near misses’?• Do you hear about near misses
anyhow else?
• How will you log those??
Collation
• How will you collect and collate this kind of data?
• Soon after the event, by reading every deviation and populating a spreadsheet?• And who will do that – SDs?
Management? QA?
• At audit, from the draft study report?
• How about all deviations begin their life in a central tool that automatically captures key details as part of completing the template?• SharePoint can do that quite easily
(or you can spend 10s of £000’s on an eQMS…)
Bottom line is this – if you don’t have the data, you can’t easily see the bigger picture
Now you’ve got some dots… join ‘em up!
Use your data
• Remember to review the combined or cumulative effect on individual studies
• Periodically sit back and look at the information you have• Is any issue more common than you realised?
• Are any factors standing out?
• Are some root causes not really getting fixed?
• Are some areas, staff or processes becoming hot-spots?
• Can the procedures that allowed ‘human error’ be improved?
• Are the checks you already have in place really effective?
What might you find?
• The same samples that didn’t get frozen from the field in the required time also suffered a freezer breakdown before they were shipped to the lab.• Then they sat unprocessed until
their stability limit.
• What value might those analytical results have now?
• Most ‘dosing errors’ are not committed by inexperienced staff. Turns out the old hands are less reliable.
• A sequence of clotted blood samples (each of which was repeated with ‘no impact’) was traced back to a common factor – one technician.
Remember that GLP is a Quality System
• So we should be looking for continuous improvement
• Just slamming the lid on every issue is self-defeating, and a sure way to see them again
