Knowledge / Scenario - Introduction of a new sterile product
“You have a new sterile product entering commercial manufacture and fill on your site. What needs to happen to implement the change and permit you to certify product?
First thoughts
Change - first principle of a QMS management system for anything different will be a change management/change control process. You mention this before anything else.
This is very much a question that is more open ended than a closed knowledge question but less “interactive” with the assessors than a true “here’s a problem” scenario.
Assumptions
For the purposes of giving the largest possible example answer I am going to use the following assumptions.
New site
First product
You should clarify these with any assessor.
The “trainee’s answer”
The approach below is actually not what I would say in a final viva. it is overly structured and long. It is how I think trainees should “drill” their thinking as they start to tackle these questions. It’s an approach that will allow someone to flesh out a very comprehensive, if overlong answer from first principles. It has the following advantages
Minimises requirement for additional memorisation
Makes use of existing answer to the legal duties question that you will have already gone through.
Is adaptable to multiple “What needs to happen/be in place to permit you to certify product? type questions.
Is a great way to drill questions as it reinforces memorisation of the legal duties and shapes your thinking ahead of a viva.
You will see the disadvantages for yourself. But
Used on its own, it may take up too much time in a viva to structure it out this way
It is not elegant, it makes you jump around a little in the QMS system
If you are too rigid in the viva, you risk giving the impression that you are too robotic in your approach.
So the approach i am showing today is really for training your mind and to provide a way to get going.
Fleshing out the answer?
In the most literal sense the question “What needs to happen to implement the change and permit you to certify product?” can be answered simply “Ensure everything in Annex 16 section 1.7 is in place”
So lets just do that.
For each of the 21 duties laid out in the legal duties in Annex 16 we need to lay out what they mean for this scenario
Now we already have a way to remember these:
1) The marketing authorisation (the MA or CTA)
o Sites comply with MA
o Processes comply with MA
o Materials comply with MA (Site and Spec) / Supplier QMS in place
o Batch in Specification to MA
o TSE compliant if in MA
2) Site licensing (think MIA, ManA)
o All sites (Manufacture/Test/AS) audited and reports available
o Self inspection is active and current
o All processes in validated state and personnel are trained.
o Supply chain available to QP
o Required technical agreements are in place
3) The falsified medicines directive
o AS complaint to GMP and GDP
o AS imported has written confirmation of GMP (if not on whitelist)
o Safety feature in place
o Agreement for dist and shipment in place.
o Excipients compliant to GMP
4) The batch documentation pack – what the qp will see at the time of release
o Manufacturing and testing are in accordance with GMP.
o All records complete and IP checks complete
o Post marketing commitments met, stability data supports investigation
o Any changes assessed and any needed checks completed
o All investigations complete to a sufficient level
o Nothing open that stops certification (complaint/recall etc)
You may have written these down when answering the first viva question. Every time you practise a question like this I would recommend writing them again.
What we are recreating is how you would answer this in a real world job - you would pull out the dog eared orange guide and use it as a guide…
Because this is a question relating to a new site we will start with that first
Site licensing (think MIA, ManA)
o All sites (Manufacture/Test/AS) audited and reports available
o Self inspection is active and current
o All processes in validated state and personnel are trained.
o Supply chain available to QP
o Required technical agreements are in place
What does this mean for this scenario question?
You have a MIA/ManA or equivalent, i.e. you have obtained a site licence
This will have required a pre approval inspection by the local competent authority to grant you a site license.
You have a site master files in place detailing the site activities, processes, major equipment etc.
Equipment brought into the site and the areas of manufacture themselves have been through a full qualification program and are validated.
This will include all sterility validation ie: Autoclaves are validated, aseptic processes are validated in at least three APS/Media fills.
You will pay special attention to utilities that support sterile areas including water systems
You have adequate people to operate the site i.e. you have enough of them (capacity) and they are adequately trained (capability). The training program is in place and fit for purpose.
Your key suppliers and contractors are on an approved supplier list and are audited with no critical findings, CAPA plans are in place.
You own internal auditing program is active and there are no open critical filings, CAPA plans are in place.
You have generated a supply chain map (upstream and downstream of your operation)
All suppliers and contractors have a quality technical agreement in place with you. both parties are meeting their obligations.
There is a written agreement regarding any shared QP responsibilities.
The marketing authorisation (the MA or CTA)
o Sites comply with MA
o Processes comply with MA
o Materials comply with MA (Site and Spec) / Supplier QMS in place
o Batch in Specification to MA
o TSE compliant if in MA
What does this mean for this scenario question?
You have a marketing authorisation for the product in question and the intended market.
The MA aligns with your production and testing methods.
You will have to have the processes transferred in under a “tech transfer” program from whomever performed the previous manufacturing/testing
The MA aligns with your source of materials and their quality. The material vendors/suppliers have passed a vendor accreditation program and have been risk assessed
You have verified the QMS of your vendors/suppliers listed on the MA. They are audited.
Any batches that you have produced and intended to sell are validated compliant to the MA and are in specification.
For material with a TSE risk, you have controls in place.
The falsified medicines directive
o AS complaint to GMP and GDP
o AS imported has written confirmation of GMP (if not on whitelist)
o Safety feature in place
o Agreement for dist and shipment in place.
o Excipients compliant to GMP
What does this mean for this scenario question?
When your AS supply has been audited you are capable of completing a QP declaration if required. Where relevant a per batch GMP certificate is beign supplied by the local competent authority
Excipient suppliers are audited against GMP if relevant
You have a validated process for the inclusion of sfatey features and adequate controls and challenge mechanisms
You have QTAs in place with your distribution and shipment partners.
GDP is compliant across the supply chain. ie
Warehouses, shipment containers and stores have been temperature mapped, worst case locations determined (usually over a year) and these locations are subject to ongoing monitoring.
Reconciliation processes are robust and in place
Dedicated areas exist for material quarantine and rejected material storage.
Measures in the warehouse are in place for cross contamination control
Material is used in a First Expiry, First Use process
Physical site security is adequate with tiered access rights for high risk areas
Pest control processes and measures are in place.
All shipment containers/lorries are physically secure with seal systems
The batch documentation pack – what the qp will see at the time of release
o Manufacturing and testing are in accordance with GMP.
o All records complete and IP checks complete
o Post marketing commitments met, stability data supports investigation
o Any changes assessed and any needed checks completed
o All investigations complete to a sufficient level
o Nothing open that stops certification (complaint/recall etc)
What does this mean for this scenario question?
Manufacturing and testing are in accordance with GMP. ie
Management is bought into and setting a Quality culture
You have a suitably resourced and scoped QMS ( Chapter 1) including procedures for
Deviation
Complaints
Recalls (and mock recalls)
CAPAs
Risk assessment
Root cause analysis
Change management
OOS/OOT
Personnel are trained, records available (Capter 2)
Facilities comply to relevant standards (Chapter 3, Annex 1 etc)
Testing labs follow GMP principles as laid out in Chapter 6.
Your EM monitoring program is risk based and active and areas are in control
There is a documentation system including procedures for reconciliation, Data integrity procedures are in place and followed
All required SOPs/work instructions/MOAs/Batch documentation packs are adequate
GAMP procedures are in place and computer systems are validated where relevant
You have an adequate stability program and batches from pre validation and validation studies are being monitored for accelerated and storage conditions
Finally - when all else in place, there is nothing (quality concern etc) that causes you to not certify.
As you can see - the question is initially daunting in its scope and quite challenging to comprehensively answer under time pressure. The key is to cover all of the big topics while remembering key specifics - something I believe this approach is going to help you to learn to do.
Its also important to remember you can’t list everything and I’m sure I have missed a few things above. If you had to list everything you would need to open the orange guide on your lap and start reading page 1 aloud.
I future I will outline some other approaches you can take to the same question type.
Disclaimer
This document is not a legal document not should it be interpreted in any fashion as a guide. This is a set of notes compiled as part of a personal training program. It is not complete or authoritative. I hope it gives you some value.
This is a personal effort and is not affiliated with my current role or employer.
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. If you use it to train someone else, fantastic, but give the QP Notebook a plug. Thanks