Hello,

Wish to hear from you who are in the pharmaceutical industry for a few specific questions on maintenance in relation to GMP.

my email: gerjes@maltanet.net

THANK YOU.

Why not ask your questions here so all can learn with shared knowledge?

That is the basic concept here.

Terry O

OK then, here it comes...

Can someone please indicate me what are the GMP requirements for maintenance, BESIDES cleaning and calibration, for a solid dose facility?

Typical equipment consist of
HVAC, purified water system, laminar flow booths, tablet compression machines, blister packaging lines, compressed air systems.

What i have found in guidelines mainly are based on requirements for designing facilities to GMP standards, although I read on ISPE that a new gudeline will be issued regarding maintenance itself. My problem is that I need this information rather fast and can't wait for this new guideline so I thought people in this industry who've been through regular audits can give me some light on it.

THANK YOU.

Rennie,

It is many years since I worked in your industry. I am only able to comment in broad terms, on principles rather than practices, so this may not be what you are seeking - my apologies.
GMP,as I recall it is designed to
- prevent contamination of products
- eliminate cross-contamination between product batches
- trace any batches that do get contaminated back to source quickly and with certainty

quote:

guidelines mainly are based on requirements for designing facilities to GMP standards

The principal activities are based on good hygiene and sanitation practices. From a maintenance perspective, HVAC, water quality, laminar flow cabinets etc are sources of contamination, by dust or bacteria. HVAC fliteration quality temperature and humidity controls, demineralizarion plant efficiency and air velocities in laminar flow cabinets are all important. These and other functions should be identified clearly and performance standards established. The functional performance should be verified periodically. Maintenance tasks have to be created, executed, measured and analyzed to ensure the performance standards are met. Good records of both operating and maintenance activities are required,as these are areas for auditing.
Your QA Department may be able to provide more detailed advice.

Hello Rennie,

you will get most of the answers from looking to your SOPs. These describe the way to work, they define whether any work is GMP relevant, whether any work has to logged.
Simply spoken any work which is product related is GMP relevant (production machines, HVAC with respect to production, ...).
On the other hand maintenance work in office buildings (changing light bulbs, repairing windows) normally is not GMP critical.

Thanks Vee & Maintiger.

Vee, from what I can see, requalification is one of the requirements which in my opinion is a validation / QA exercise. Maintenance carries out the routine monitoring of the operation of systems according to the pre-established limits.

Maintiger, my question arises from the fact that this is a new plant at the stage where SOPs are still being written.

I understand that there are the manufacturer's recommendations but we are all pressed to be effective and carry out maintenance for "specific" reasons or objectives which in this case GMP would be one of them. For this I wish to have indication about these practices.

We've read it or heard it many times.....Does this task address an objective e.g failure Yes/NO. If No then don't do it...it's a waste of resources.

So any indications what these GMP requirements would be?

Thank you.

Rennie,

Auditors will look for
- procedures being followed correctly
- records being kept
- horizontal surfaces being free of dust
- room corners being clean
- good housekeepping, especially during and on completion of maintenance
- food grade lubrication used where required
- loose paint film
- cobwebs (yes!)
- HVAC filter condition
- demin water sample test results
- ceiling tiles properly in place
- entry points of air, water, vacuum, cabling etc. properly sealed off
and similar, rather like what you you would expect in a hospital. If you follow the principles, you will be able to think of the details. Your Production Manager will also be able to assist.

Sorry the delay, I was off the plant.
First, get a copy of the regulation: 21 CFR Parts 210 and 211, read it, understand it, be able to remember where the critical paragraph impacting maintenance are and what they say. You got to know the law to be able to comply to it.
Main topics to study:
* 21 CRF 211 Subpart C Building s & Facilities
* 21 CFR 211 Subpart D Equipment
* 21 CFR 211 Subpart F Production and Process Control: 211.100, 211.105
* 21 CFR 211 Subpart J Records and Reports
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FACILITIES:
* You need a SOP for your Housekeeping Program of facilities. Records of housekeeping of critical areas (you and QA need to define which one are those) need to be kept according to Subpart J.
* You need a SOP for your Pest Control Program.
* You need a procedure to comply with 211.58 which require that the facilities are maintained in a "good state of repair". You have to define how you do that. With PM? then you need a SOP for your PM Program. Do you also need Corrective Maintenance to maintain the "good state of repair"?, then you will need another SOP. All related records shall comply with Subpart J.
---
INSTRUMENT
* You need a SOP the Calibration Program (definitions, classification of instruments, calibration points, how it is scheduled, responsibilities of affected personnel (instrument owners, maintenance, QA), internal/external calibrations, labeling, records, etc.
* At our plant we have several other calibration SOPs to detail the instructions on how to calibrate indicators, transmitters, transducers, etc. They are written in a way to be applicable to a large number of instruments within the same category. If we encounter an instrument that can not be calibrated with the "general" procedure we write an specific SOP for this model. Our calibration orders instructions simply say "Calibrate the instrument", and provide the SOP number, calibration points, and tolerance.
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EQUIPMENT
* For equipment maintenance you will need a PM SOP. It might be the same SOP used for facilities PM.
* We do not have individual SOPs for all types of equipment (Tablet Press, Tablet Coaters, Fluid Bed Dryers, etc.) We use the task lists of our CMMS as the written procedure where there are the details on how to perform the maintenance. If for a specific maintenance additional information is required we add to the task lists references to the equipment manual or to a specific SOP.
---
HVAC
* Besides PM / calibration for all HVAC equipment/instrumentation, do you have HEPA filters? Then FDA will expect that you certify them when installed and with some established frequency.
---
211.105 Equipment numbers must be unique:
* Never reassign an equipment number.
* Ensure equipment numbers are not repeated.
---
RECORDS
* Can be hardcopy or electronic; however if electronic records you have to comply with Part 11. If at the validation of your CMMS, it was proven to be in compliance with the electronic signatures/records regulation then you can use that.
* If not you have to keep the original hardcopies of your documentation and write SOPs on how do you will do that: how the records are organized, where, for how long, will you keep them in file for two years and then transfer to an archiving area? Destruction of records after N years or certain categories of records will never be destroyed? check with QA.
Keep: Housekeeping records, Pest Control Records, PM orders, Corrective Orders, PdM orders?, Instrument Calibration orders and certificates.
* Keep: records of equipment / instrument record creation at CMMS, PM task lists, change control records.
---
The main thing is describe what you do in your SOP and more important DO what you WROTE that you would do. The FDA will not tell you that you have to change the filter every three months, but if you wrote that in an SOP, you better be able to prove (with records) that you changed the filter every three months.

This message has been edited. Last edited by: Eugene,

quote:

We've read it or heard it many times.....Does this task address an objective e.g failure Yes/NO. If No then don't do it...it's a waste of resources.

To start, the FDA does not look on your finances; cost issues (waste resources) are not important to them. Never tell an inspector you did not did something because it was expensive!!!

You have to prove with your maintenance program records that:
* malfunctions are prevented (211.67)
* contamination is prevented (211.67)
* proper equipment performance is ensured(211.68)
If a task in your equipment maintenance aid you to prove FDA what they want, it is not a waste resource.
Another GMP: 211.25c FDA expect you to have adequate quantity of personnel to perfom and supervise the maintenance (part of processing the drug product). Large backlog, or orders pending for supervisor signature may hint them you need more personnel.

This message has been edited. Last edited by: Eugene,

I left the pharmaceutical industry a year ago and I think Eugene has covered the requirements very well. Having been engaged in attempting to modernize maintenance practices, I discovered that the company had been very thorough in their description of systems. This made any upgrade of equipment or procedures very expensive. For example, if you have a system that is driven by a 50 HP induction motor, avoid going any farther than that in the description or you have to do a change to go from a Reliance to a G.E. motor. This is particularly when a piece of equipment is no longer manufactured. You have to go through a lengthy change process to put the replacement item into your procedures. Even worse, if that item is part of a process SOP, you may have to revalidate the whole SOP. This is not a simple QA exercise. I think it is admirable that you are trying to get ahead of the game on writing SOP's but definitely look at the laws first. Failure to comply is extremely expensive.

Ken Culverson

Thanks Ken, hope this is useful to Rennie. I will be out of touch until 31 July, but will be glad to answer any questions.

This message has been edited. Last edited by: Eugene,

Practice: avoid entering cardboard boxes (like boxes where the spare parts come from your supplier) to the process areas.
Why? There are some insects that hide inside of cardboard and you do not want them inside a pharma drug packaging line.

I think for ISO9000, the idea " Do what you write and Write what you do" is already obsolete. The new revision of ISO9000 Year 2000 concentrates on the PDCA (Plan, DO, Check & Act) cycle. For precedure writing, business process maps are sufficient with brief descriptions if necessary. This will facilitate easy amendments for continuous improvement.

My understanding is that the above change in philosophy is necessary because we do not want auditors come to our facilities and audit whether We do what we write or Write whatever we do. Instead the auditors should focus on whether the work processes deliver the business objectives or not and any improvements being done or not.

This message has been edited. Last edited by: Josh,

Hello there,

Thanks for all your informative contributions.

Eugene, for the task list mentioned from the CMMS, is there an example of any task performed for GMP reason only.

"malfunctions are prevented - 211.67", how can one prevent all mulfunctions?

A maintenance process mapping with brief description will not meet FDA's GMP requirement at 211.67 Equipment cleaning and maintenance, to have (and follow) written procedures with "a description in sufficient detail of the methods, equipment, and materials used in the cleaning and maintenance operations, and the methods of disassembling and reassembling equipment as necesarry to assure proper cleaning and maintenance".
The maintenance process mapping may be (we do) included at the Preventive Maintenance Program procedure as an appendix, but by itself is not enough to meet regulations requirement.
Is FDA's obsolete according to ISO9000? Maybe, but still we have to comply with their requirements if we want to sell phamaceutical drugs in the USA. Not only that, many other countries use FDA's regulations as a basis for their own pharma regulations. Then meeting FDA's requirements open not only the pharma drugs USA market (near 50% of total world market) but those other countries' markets as well for your products.

This message has been edited. Last edited by: Eugene,

quote:

Originally posted by Rennie:
"malfunctions are prevented - 211.67", how can one prevent all mulfunctions?

If you find a set of PM instructions that executed properly at the given frequencies, will prevent all the malfunctions of a solid dose pharma equipment please let me be the first to know.
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FDA (and your QA department also) will expect that you modify the PM instructions to include tasks to prevent a new malfunction that was discovered. If that is not possible, then be prepared to explain how your company ensure that the quality of the product going out to the public is not affected by the equipment malfunction.
* Alarms?
* Product reject mechanisms?
* Operator Visual Inspection? Digital Vision Systems?
* Lab analysis?

for the current text of the GMP:
http://www.fda.gov/cder/dmpq/cgmpregs.htm

Are the mechanics/technicians working in outside areas / gray areas, the same mechanics/ technicians who will enter the process areas?
* Check with Operations / QA applicable gowning/degowning procedures.
* Cleaning/desinfect parts and tools before entering the process areas; or
* Separate a dedicated set of tools for process areas, different to those used at utilities areas?

Hello Eugene,

Thank you again for your very informative information.

Regarding tools, we shall be using a seperate dedicated set located inside the production area.

Pest Control Program / SOP
* Scope:
*** Which kind of pests do you need to protect your facilities: insects, rodents, birds?, others?
* Who will be doing it? A contractor supervised by Maintenance?
*** Verify that their licenses/qualifications required from your goverment health agency are in order before each service.
*** Keep a copy of those in your file.
* Which pesticides will be used?
*** do you allow your contractor dilute the pesticide within your facility?
*** where will be applied?
*** how often?
*** If you have a rain event 1 hour after the exterior perimeter spraying, do it need to be repeated?
*** rotation of pesticides every three months?
*** special care to avoid contamination of materials, pasckaging components, etc.
* Other pest control devices?
*** Which?
*** Where are located?
*** Maintenance/cleaning?
*** What will you do if (for example) you notice rodent activity in a rodent bait station located near an entrance to the facility?
* Special services
*** Need pre-authorization from ???
* Records:
*** must comply with 21 CFR 211 Subpart J
*** Include sample forms as appendices of your SOP. Include instructions on how to fill them at the SOP.
*** which data must be recorded?
1. Date of service
2. Areas serviced
3. Pesticide(s) used
4. Comments on findings
5. Corrective actions (document maintenance order number as applicable)
6. Signature/date of who performed the service.
7. Signature/date who witness the service
8. Signature/date who approved the document