21 CFR 820 - Stability and Validation Requirements

J

Jim-S

#1
My company recently took ownership of a medical device product. This product is manufactured in two parts that are later packaged together as a kit. Our plan is to switch the manufacturing of one of those parts (a biologic in a syringe) to our manufacturing site. As part of this process we are planning on manufacturing product for stability.

Our management representative (the Director of Quality) has stated that he would like 3 lots of product for stability. The problem is that the VP of Manufacturing is objecting. The VP of Manufacturing feels, based on the fact that the FDA doesn't require 3 batches, that only one batch is required by the FDA for a change in manufacturing site. The VP further stated that "It doesn't matter what [the Management Representative] thinks."

Does anyone have any opinions on what the FDA would normally be look for? Couldn't only one batch pose a possible delay to the site transfer?
 
Elsmar Forum Sponsor

GStough

Staff member
Super Moderator
#3
My company recently took ownership of a medical device product. This product is manufactured in two parts that are later packaged together as a kit. Our plan is to switch the manufacturing of one of those parts (a biologic in a syringe) to our manufacturing site. As part of this process we are planning on manufacturing product for stability.

Our management representative (the Director of Quality) has stated that he would like 3 lots of product for stability. The problem is that the VP of Manufacturing is objecting. The VP of Manufacturing feels, based on the fact that the FDA doesn't require 3 batches, that only one batch is required by the FDA for a change in manufacturing site. The VP further stated that "It doesn't matter what [the Management Representative] thinks."

Does anyone have any opinions on what the FDA would normally be look for? Couldn't only one batch pose a possible delay to the site transfer?
The number "3" seems to be a magic number when it comes to doing validations (and maybe stability) in the pharma and medical device industries. The reason for this is that if the process (or whatever is being validated) can be repeated with the same results each of the 3 times, then it is accepted that it will continue to be reliable and can therefore be validated. If you only use 1 batch to do the stability and/or validation of your product, then you don't really have the assurance that it will continue to produce the expected results each time.

This is the way I have understood this, but perhaps someone else may have a better explanation and examples to illustrate.

I hope this helps, at any rate. :bigwave:
 

Ajit Basrur

Staff member
Admin
#4
FDA honors the ICH Q1A(R2) Stability Testing of New Drug Substances and Products that states the following -


Selection of Batches (2.1.3)

Data from formal stability studies should be provided on at least three primary batches of the drug substance. The batches should be manufactured to a minimum of pilot scale by the same synthetic route as production batches and using a method of manufacture and procedure that simulates the final process to be used for production batches. The overall quality of the batches of drug substance placed on formal stability studies should be representative of the quality of the material to be made on a production scale.

Other supporting data can be provided.​

Three batches are ususlaly taken to understand the batch to batch variation - when you take one batch for stability testing, it doesnot provide good assessment of batch to batch variation while 2 batches is considered unreliable estimate.

Hence 3 batches are required as per most regulatory agencies like FDA and ICH guidelines.
 
A

achorste

#5
Normally I go with the typical '3 batch rule' - although this isn't stated anywhere in our procedures / standards - as mentioned above it gives an understanding of batch to batch variation (we normally run each batch of the 3 on different shifts with different operators).

However - we also do what we call "extended PVE" - a bastardisation of Depuy's process verification activities where we use one large batch (typically >= 2x normal batch size) to provide process capability data in order to estimate long term process capability and approval for manufacture. Then the subsequent 3 production batches have tighter inspection requirements to confirm stability.

It isn't the best method, but it's a compromise that seems to work.

Of course that is medical device contract manufacturing (not special process validation) rather than pharmaceutical, it may not apply, but that's my 2 cents worth.
 

Weiner Dog

Med Device Consultant
#6
Traditionally, everyone uses the 3-batch rule re pharma. However, with PAT http://findarticles.com/p/articles/mi_hb5677/is_6_6/ai_n29111087 , FDA is starting to steer away from this. The medical device world is a different story. One has to use risk management and statistical techniques, taking into consideration criteria such as the cost and time to manufacture one lot/batch.unit, in order to determine the sample size. If you use the 3-batch rule re a medical device, then you have to justify it using a valid statistical technique.
 
G

gholland

#7
What else has your company done to establish the variability of the process? The reason for multiple lots is to study process variability.

Have there been IQ/OQ/PQ Validations done on the process in the new facility? Are the tools the same? Is the equipment the same as the first site meaning you took the machines from facility 1 and use them in facility 2? If you're running on different equipment then you need more testing then just a single run and calling it good. Can you demonstrate the new process meets all of your requirements? If not then the company is just setting itself up for a spanking by an auditor.

:2cents:
 
J

Jim-S

#8
Thanks to everyone for the feedback! - In follow-up, my company has decided to go ahead and produce one exhibit batch that will be put up on stability. This will be followed by 3 validation batches at a much later date (2010). - Unfortunately, I don't think that my company has done any work to demonstrate reproducability. We seem to be proceeding based on the idea that nothing could possibly go wrong.

Just to give you the clearer picture of the situation that I am dealing with, decision making at my company appears to be largely based on who barks loudest. It is a pack mentality & right now the VP of Manufacturing is "top dog". The problem is that this VP refused to attend our site training on 21 CFR 820, so he doesn't have any basis for the decisions that he is making. - Last week we had a meeting that the VP attended during which we all agreed to fill this material in late January of 2009. Then, early yesterday, this VP decided that we would instead fill the material at the end of this week. We don't have a protocol ready, so he decided that we don't need one. - Our VP of Quality and our Director of Quality are unwilling to object. Everyone else is trying to establish their "don't blame me" defense.

This is our first venture into the medical device world. The product will need to be compliant with 21 CFR 820 and ISO 13485.
 
G

gholland

#9
Not to sound overly harsh... but...Good luck with the upcoming audit and 483 warning letter. Because your company is a new medical device supplier FDA will be interested in the quality systems and wanting to audit your compliance not only to FDA requirements but your own systems. If your upper management isn't even willing to get trained in the 21CFR820 requirements then your company is in for a shock. That VP may be top dog but the FDA auditor works for Animal Control.

The FDA won't care what your management excuses are. Your firm is in violation of FDA rules just from the lack of management training and management support without even looking at the lack of Validation work.

If this is your firm's first foray into the medical device world they may wish to reconsider that decision judging by the response. Medical device require a different mindset that is dedicated to compliance with FDA/ISO requirements.

Perhaps go to the FDA website, print out some 483 warning letters and/or the QSIT manual and leave them anonymously on desks.
 

Stijloor

Staff member
Super Moderator
#10
<snip> Just to give you the clearer picture of the situation that I am dealing with, decision making at my company appears to be largely based on who barks loudest. It is a pack mentality & right now the VP of Manufacturing is "top dog". The problem is that this VP refused to attend our site training on 21 CFR 820, so he doesn't have any basis for the decisions that he is making. - Last week we had a meeting that the VP attended during which we all agreed to fill this material in late January of 2009. Then, early yesterday, this VP decided that we would instead fill the material at the end of this week. We don't have a protocol ready, so he decided that we don't need one. - Our VP of Quality and our Director of Quality are unwilling to object. Everyone else is trying to establish their "don't blame me" defense.
Just make sure your resumé is up to date! ;)

Stijloor.
 
Thread starter Similar threads Forum Replies Date
A TUV Audits - 21 CFR 820 General Auditing Discussions 6
S Records - Do's and don't' of record entries (FDA - 21 CFR 820) Records and Data - Quality, Legal and Other Evidence 13
T 21 CFR 820.20 - Quality Planning Requirements? 21 CFR Part 820 - US FDA Quality System Regulations (QSR) 2
M 21 CFR 820 vs 21CFR820 vs 21 CFR Part 820 Document Control Systems, Procedures, Forms and Templates 3
A 21 CFR 820 - Risk Management - Looking for some guidance US Food and Drug Administration (FDA) 3
P Equipment 21 CFR 820.70(g) - User Requirements Document for Off the shelf equipment 21 CFR Part 820 - US FDA Quality System Regulations (QSR) 7
D ISO 13485, FDA 21 CFR 820 and Auditing the Accounting Department ISO 13485:2016 - Medical Device Quality Management Systems 5
Ed Panek 21 CFR Part 820 - FDA Label Requirements 21 CFR Part 820 - US FDA Quality System Regulations (QSR) 8
R Addressing training requirements - 21 CFR Part 820.25 (1) & (2) Other US Medical Device Regulations 4
R How to improve a Validation program and procedures to FDA (21 CFR part 820) & ISO13485 21 CFR Part 820 - US FDA Quality System Regulations (QSR) 3
Marc Problem with 21 CFR Part 820 - US FDA Quality System Regulations (QSR) sub-forum link - 2 May 2019 Elsmar Cove Forum Suggestions, Complaints, Problems and Bug Reports 1
R 21 CFR Part 820 Contract Manufacturer of Medical Device Component 21 CFR Part 820 - US FDA Quality System Regulations (QSR) 4
N Change Control - Compliance with FDA 21 CFR Part 820 Document Control Systems, Procedures, Forms and Templates 3
D 21 CFR Part 820 (Subpart A) - Question about "Authority" 21 CFR Part 820 - US FDA Quality System Regulations (QSR) 2
R RUO audits - CFR 820.22 and ISO 13485 8.2.4 Internal Auditing 3
A Training as well as certifications for ISO 13485:2016, 21 CFR 820... Training - Internal, External, Online and Distance Learning 5
K Production Unit Labeling - 21 CFR 820.184.e 21 CFR Part 820 - US FDA Quality System Regulations (QSR) 5
R 21 CFR Part 820.186 - Types of Quality System Records Document Control Systems, Procedures, Forms and Templates 1
M Does the Scope of 21 CFR Part 820.72 (Equipment) apply to Design? 21 CFR Part 820 - US FDA Quality System Regulations (QSR) 4
V 21 CFR 820 Compliant way to use Kaizen to address Nonconformances Nonconformance and Corrective Action 9
C 21 CFR Part 820.184 - Label Requirements ISO 9000, ISO 9001, and ISO 9004 Quality Management Systems Standards 9
shimonv 21 CFR 820.20(d) says: Each manufacturer shall establish a Quality Plan 21 CFR Part 820 - US FDA Quality System Regulations (QSR) 4
V Upgrading Systems from CFR 211 to CFR 820 (drug+device combination) 21 CFR Part 820 - US FDA Quality System Regulations (QSR) 7
S Looking for a checklist comparing ISO 13485:2016 and 21 CFR Part 820 ISO 13485:2016 - Medical Device Quality Management Systems 14
Q Internal Audit of Product Quality Complaint System (21 CFR Part 820) Customer Complaints 9
R Managing Employee Training Files - 21 CFR Part 820.25 21 CFR Part 820 - US FDA Quality System Regulations (QSR) 4
M Release authorization before or after packaging per 21 CFR 820.80(d)? 21 CFR Part 820 - US FDA Quality System Regulations (QSR) 4
D Need advice in streamlining antiquated 21 CFR 820 compliant QMS Quality Manager and Management Related Issues 2
J Minimum staff per 21 CFR Part 820 21 CFR Part 820 - US FDA Quality System Regulations (QSR) 2
M Does a process map satisfy 21 CFR 820.20(d) (Quality Plan)? 21 CFR Part 820 - US FDA Quality System Regulations (QSR) 4
R Calibration of processing equipment - 21 CFR 820.70 Production and process controls 21 CFR Part 820 - US FDA Quality System Regulations (QSR) 3
M Issues with UDI additions to 21 CFR 820 requirements 21 CFR Part 820 - US FDA Quality System Regulations (QSR) 2
M Interpreting Process Controls - 21 CFR Part 820.70(a) 21 CFR Part 820 - US FDA Quality System Regulations (QSR) 5
S How others have defined "reaudits"? 21 CFR Part 820.22 Internal Auditing 1
M FDA 21 CFR 820.250 - Does "valid statistical" always mean math? 21 CFR Part 820 - US FDA Quality System Regulations (QSR) 6
J Document Control Features (Document Content Requirements) and 21 CFR 820.40 21 CFR Part 820 - US FDA Quality System Regulations (QSR) 4
S 21 CFR Part 820.40(b) Clarification on Required Document Approvers 21 CFR Part 820 - US FDA Quality System Regulations (QSR) 3
R Where to find 21 CFR Part 820 Translated into Czech, Spanish, and German 21 CFR Part 820 - US FDA Quality System Regulations (QSR) 1
N Certificate of Compliance from a Sister Company for FDA 21 CFR 820 Exemption 21 CFR Part 820 - US FDA Quality System Regulations (QSR) 1
S Does FDA expect suppliers to be independently assessed to 21 CFR Part 820 ? US Food and Drug Administration (FDA) 4
A Effective Date (of Documents) issue outlined in 21 CFR Part 820.4 21 CFR Part 820 - US FDA Quality System Regulations (QSR) 11
L Mobile Medical App - Understanding 21 CFR Part 820 Requirements 21 CFR Part 820 - US FDA Quality System Regulations (QSR) 3
T "Special Process" Validation Requirements (21 CFR Part 820) 21 CFR Part 820 - US FDA Quality System Regulations (QSR) 15
Y ISO 13485:2003 &FDA QSR (21 CFR 820) Quality Manual,34 Procedures and Form Book, Video, Blog and Web Site Reviews and Recommendations 8
R Policy Statement for FDA CFR 820 Acceptance Activities of Incoming Products. Other US Medical Device Regulations 1
shimonv Storage of finished medical devices per 21 CFR Part 820.150 21 CFR Part 820 - US FDA Quality System Regulations (QSR) 9
M Does 21 CFR 820.80 (b) require a Supplier to have Receiving Inspection? 21 CFR Part 820 - US FDA Quality System Regulations (QSR) 13
I Does being a subsidiary fully absolve company B from complying with 21 CFR 820? 21 CFR Part 820 - US FDA Quality System Regulations (QSR) 4
A Help me understand the applicability of 21 CFR Part 820.198 (Customer Complaints) 21 CFR Part 820 - US FDA Quality System Regulations (QSR) 3
A Do controlled documents require a signature on every page as per 21 CFR 820.40? 21 CFR Part 820 - US FDA Quality System Regulations (QSR) 5

Similar threads

Top Bottom