In order to guarantee the observation of the requirements on medicinal
products and those laid down in the GMP regulation, the supervisory
authorities regularly conduct inspections. The focus is not only on the
process, the documentation or on validation. Today, it is shifting more
and more towards pharmaceutical engineering. The equipment and the
pharmaceutical facilities as well as HVAC systems can have deficiencies
that may be discovered by the inspectors. Therefore, it becomes more and
more important to have a close look at the buildings and equipment and to
question internal procedures.
you know your facility inside out?
Just try to find the answers to the following small GMP compliance
checklist on Design and Construction of Equipment:
- How do you prevent cross-contamination by air?
- How do you handle deviations in qualification?
- Requalification: Test scope, frequency, responsibilities?
- Do you have reports on changes and deviations regarding your HVAC
system? => Requalification?
- How do you check your warning systems?
- Do you have a monitoring procedure?
- How do you maintain the validation status of your water system?
- Do you have an SOP describing your sampling method?
- Which limits have been defined?
- Do you analyse the feed water?
- Do you calibrate your measuring systems regularly?
These are just some questions that may be asked during an inspection.
Could you answer all the questions? No?
If you have a close look at the warning letters addressed to drug
product manufacturers in Fiscal Year 2004, you will find that deficiencies
concerning buildings and equipment are among the top ten deviations.
Therefore we organise a 4-day intensive training course on FDA
and EU-GMP Compliance in Pharmaceutical Engineering in Barcelona.
In the following we have listed the original quotations regarding
21 CFR 211.42
"Design and Construction Features".
Failure to conduct repacking of penicillin and repacking of
non-penicillin drugs in separate facilities. [21 CFR 211.42(c) and
Penicillin products, cephalosporin products, and non-beta-lactam
drug products are processed in the same facility at your firm.
Although penicillin and non-penicillin beta-lactam drug products are
repacked in a dedicated room, the room is not designed to prevent
air migration, nor have sufficient controls been established to
prevent the exposure of non-beta-lactam drug products to
cross-contamination. In addition, containment procedures have not
been established to assure that employees, in moving about the
plant, do not carry residue from penicillin/non-penicillin
beta-lactams into nonpenicillin areas. This separation (penicillin
room) is ineffectual given the lack of containment procedures and
practices observed by the investigator. For example, employees are
allowed to repack non-penicillin and non-beta-lactam drug products
after re-packing penicillin and/or non-penicillin beta-lactam drug
products; employees do not change work apparel between packing
penicillin drug products and non-penicillin drug products; employees
move throughout the facility without restriction and share common
areas, such as cafeterias and restrooms without re-gowning.
Failure to separate completely the air handling systems for the
packing of penicillin products and non-penicillin beta-lactam drug
products from non-penicillin drug products. [21 CFR 211.42(c) and
The same air handling system is used for the repackaging of
penicillin and cephalosporins in violation of 21 CFR 211.42(c) and
There is a failure to develop control systems for your operation
as are necessary to prevent contamination of the aseptic processing,
which includes a system for monitoring environmental conditions. [21
No evaluation has been performed to show the adequacy and
efficacy of the cleaning and disinfection process used in parenteral
filling room [
] as specified by SOP [
] [21 CFR
Investigations of a batch failure or any of its components
processed in the aseptic processing area did not extend to other
drug products that may have been associated with a specific failure
or discrepancy. The heat exchanger used in the Small Volume
Parenteral manufacturing rooms [
] was found to be contaminating
the water for injection (WFI) with bacteria. The failure
investigation did not extend to reviewing the possible impact on
other previously manufactured drug products. In addition, the heat
exchanger continued to be used to manufacture other parenteral
products after the equipment was identified as being contaminated.
Furthermore, the filter integrity test procedure outlined in SOP [
does not specify a limit on the number of times a filter can be
flushed or rewetted. [21 CFR 211.192 and 21 CFR
Failure to perform operations within separate or defined areas or
to use other control systems as are necessary to prevent
contamination or mix-ups [21 CFR 211.42(c)].
For example, cans of a raw material labeled as "Benzyl
Peroxide" being held pending sampling and testing were observed
outside of the quarantine area on the same shelf as lots of the same
material that had been released for use (21 CFR 211.42(c)(1)). In
addition, barrels of rejected [
] were stored in the QA released
raw materials storage area (21 CFR 211.42(c)(2))
The flow of drug product containers, closures, and drug products
through the building is not designed to prevent contamination (21
Specifically: Sterilized glassware (including mixing beakers and
product vials), containers of sterilized product, and bags of
sterilized stoppers are carried through the unclassified workroom
and the class 10,000 compounding room in order to get them into the
filling room. The hot air ovens and autoclaves do not open into the
Control systems for monitoring environmental conditions during
aseptic processing operations are inadequate (21 CFR
Specifically: Environmental monitoring for filling operations
does not include the operator's gown and gloves.
Failure to have control systems necessary to prevent
contamination during the course of aseptic processing operations,
including an air supply filtered through high-efficiency particulate
] filters under positive pressure [21 CFR
manufacture of your ophthalmic drug products is not conducted in a
controlled room environment or under appropriate [
] filtered air
supply necessary to prevent contamination.
Your firm failed to establish a system for monitoring
environmental conditions in the aseptic, processing area as required
by 21 CFR 211.42(c)(10)(iv). Specifically,
routine environmental monitoring of the aseptic filling area for
viable and non-viable particulates is not done. Routine
microbiological monitoring of the gowns and gloves of the employees
working in the class 100 area is not done. [Reference: Form FDA 483,