What do the cGMPs mean by separate facilities? Please suggest what is minimum distance required between beta and non betalactum building?
Dedicated or Seperate Facilities as per GMP means:
- Seperate Buildings for Storage, Handling ,Dispensing,(process handling)Manufacturing, Packing & Despatch of products (Betalactums must be seperated from other products).
2.All utilities must be seperate.Except electricity.
3.Canteen and recreation facilities must be seperate too.
4.The dedicated facility must be minimum 40 to 45 meters from other manufacturing facility to prevent any entery of dust by means of Labour, Materials or even AHU’s.
Does separated facitility always refer to separated building? I heard that corticosteroids in several country should be processed at separate facility but could still under the same building with other (non-betalactams) facility.
Seperated facilities means -Seperate Buildings, Utilities and Canteen for staff. The reason is the product might be exposed to another product by means of fine dust that is comming from Operators/Staff, Equipments and or Ambient air(HVAC).
For example Penicillins cause severe anaphlytic reactions in humans.When they make cephalosporins or Carbapene drugs they have seperate facilities.This is done only to reduce risk on patients.
Cephalosporins, Corticosteroids, Anti neoplastic drugs, Carbapenes,Beta Lactum, Hormones must have seperate facilities. The reason is to prevent drug cross over even in minute quantities.
If they are manufactured under Non Beta lactum facilities or Non-APA(PENICILLIN) DERIVED facilities proper risk evalutaion must be done or proper area classification and movements must be shown.You can manufacture if you show you have proper control measures or proper containments. These days manufacturing companies are using Isolators for such casses.
Anti-cancer (anti neoplastic drugs) must have seperate facilities.
I would like to know if we formulate a hazardous material (e.g) Cephalosporins, Corticosteroids, Anti neoplastic drugs, Carbapenes,Beta Lactum, Hormones in the Non beta lactam facility - 1) Will the reg agencies like US FDA or EMEA approve the facility 2) what kind of validations data do we need to generate?
1.You cannot formulate all these product under one roof that too in a Non-Betalactum facility.
2.Even if you formulate in a specially designed facility you must show a how you prevent cross contamination of active materials between these products from Dispensing, manufacturing, primary packing, secondary packing, handling and operator-machine interventions?
3.Each individual agency will qualify your facility independently as there are differences in building designs between al agencies you mentioned.
4.For such a kind of facility you are speaking, you need most exhaustive validation documentation.You must prove that your products are non contaminated by product cross overs.
5.No one makes all these products under a single roof.
You will be handling most challenging facility, validation and approval regiems.
What if the manufacturer have few potent drugs which come in single & combination. What is the rule applied here? What is the reference?
Technically if you serach the rule books you will never find names of any drugs.You must look manufacturing of same classification of drugs.You cannot manufacture different classes of drugs either in Bulk or Formulation facilities where there is risk of cross contamination.
But there are exceptions. Recently I came across a facility in USA who is manufacturing both Hormones and Cytotoxics Formulations in the same facility.(Under same roof I mean)
They have different AHU’S
Different Material and men flows
All the process from Sampling to formulation is done under C-RABS
All process is properly mapped for Risk and the critical control points are Identifiied.
All the wash and waste materials are properly decontaminated and sent to severage.
All personnel have trained as per OSHA and E&HS.
Regular OEL minits are PEL limits are checked in both sections.
They have dedicated machines for these purposes.
They have dedicated people working in dedicated areas with out cross-ups or mixups.
The water system is having a NRV at all positions in the loop to prevent any criticality.
If you look my above statements , it gives an idea how the patient safety is not compromised during manufacturing. Both operator and patient safety is important as per ICH Q9 guidelines. It all points to “Nothing is impossible if you show FDA that cGMP is not compromised at any point”.
Got it Mr. Prasad. Even though flexibility was applied here, it comes back to the sciences and logic thinking. I do think that same rules applied to other grey area in GMP discipline. If you can justify and scientifically prove it, even the most stringent auditors in the world will accept it.
Recently I’ve noticed that the discussion of separate facilities is getting deeper, especially on Beta-Lactam group.
i. One may suggest that a group of Beta-Lactam can be produced under one roof.
ii. While another person have suggested that each group such as Penicillin, Ceph & Penems need to have separate buildings.
iii. I’ve also received some suggestion that penems can be produced in either Penicillin or Ceph facilities.
From my point of view, either Penicillin, Cephalosporin, or Penem, they should be produced in their own isolated facilities. But again it is not a simple statement. We need to look on overall issue such as utilities, personnel, material flow, labs, risk assessment, etc…
To all my GMP colleague, may I know what is the acceptable practices in your country?
Thanks in advance.
I advice you to look into latset FDA guidelines on penicillin and related products. This was published during May-june 2011.
It gave very clearly the subclasses.
I would like to ask you how a Penem can be manufactured in same facility either Penicillin or Cephalosporin? It has entrirely new starting material called 4AA.
4AA is a final product after from 6APA. Till the final 4AA there almost non-GMP regulations are being followed in ASEAN, China and Indian subcontinent till day.
4AA is obtained after 11 or 13 key steps and about 8 tons of 6APA would be producing rougly about 3.5 to 4 tons of 4AA.
You can compare the structures and Activity relationships of 6APA and 4AA.
Still it is not well documented that 4AA might or will cause any allergic or anaphylactic reactions in Individuals.
Penems acts primarily on lung infections.
No chances should be taken. This is basic idea of Product-Patient risk compliance.
Many people interpret these in many ways as per their exposure and experience.
The ultimate price will be paid by the enduser when he takes this IM shot.
Various GMPs in various parts of the globe have different interpretations.
We should act wisely on this regulation and compliance for manufacturing Penicillin and related products.
Can you clarify me that which guideline mention about the distance between Beta-lactam and Non- Betalactam.
I couldn’t find any guidance about the required distance. But here are a few other references to look up.
Here is the FDA 2013 guidance which was referenced in the discussion above: http://www.fda.gov/downloads/Drugs/.../Guidances/UCM246958.pdf
I think many factors come into play regarding “separate facility” (not just distance) and might include:
People showering upon exiting the penecillin faciliy.
Dedicated uniforms/shoes for the penecillin facility, which are different than uniforms for the other areas.
Complete segregation of materials/tools/components between the facilities.
Scrubbing air handling unit exhaust (using ULPA’s rather than HEPAs).
Waste streams (make sure any waste from the penecillin facility doesn’t go near the other facility).
You can also review Health Canada’s Guide 28 on cleaning validation which states cytotoxic agents may be required to be manufactured in dedicated facilities.
But the Guide says nothing about separation of facilities.
How about dedicated facilities for the biotech product? E.g.:
- Vaccines vs. Monoclonal AB vs. Others
- Different type of vaccines cell lines: mamalian vs bacteria vs insects vs plants vs etc?
I believe that we can share a biotech facility provided strict practice was in place to prevent cross contamination. This can be achieved by normal practice such as campaign basis, cleaning validation, good design, etc…
Probably. But this depends on your ‘risk’ analysis (RAMPP) and the molecule’s toxicity (ADE or acceptable daily exposure). Since some enzymes are missing from individuals (cystic fibrosis…) and are found in other individuals at physiological levels, I would think cleaning validation of enzyme replacement therapy (ERT) should be based on the TDD (therapeutic daily dosage).
Vaccines (no matter what origin) are at ug levels so I would think compliance with PDA TR #49 is sufficient.
This is correct. I’ve been places where mammalian and yeast cells were the technology. The segregation was very thorough, including tri-clamps being stamped and dedicated to one area or the other. It was a huge regulatory hurdle as well, and at times might not have been worth the trouble. But it has been done.
could you please explain the guidelines which taken as reference to identify that the distance of the dedicated facility should be minimum of 40 to 45 meters?