FDA Findings During Inspections on Design and Construction of Equipment

GMP News No. 525

7 March 2005

FDAFindings During Inspections
on Design and Construction of Equipment

In order to guarantee the observation of the requirements on medicinalproducts and those laid down in the GMP regulation, the supervisoryauthorities regularly conduct inspections. The focus is not only on theprocess, the documentation or on validation. Today, it is shifting moreand more towards pharmaceutical engineering. The equipment and thepharmaceutical facilities as well as HVAC systems can have deficienciesthat may be discovered by the inspectors. Therefore, it becomes more andmore important to have a close look at the buildings and equipment and toquestion internal procedures.

Doyou know your facility inside out?

Just try to find the answers to the following small GMP compliancechecklist 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 HVACsystem? => 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?


In the following we have listed the original quotations regarding21 CFR 211.42"Design and Construction Features".

Original Wording

Failure to conduct repacking of penicillin and repacking ofnon-penicillin drugs in separate facilities. [21 CFR 211.42(c) and(d)]

Penicillin products, cephalosporin products, and non-beta-lactamdrug products are processed in the same facility at your firm.Although penicillin and non-penicillin beta-lactam drug products arerepacked in a dedicated room, the room is not designed to preventair migration, nor have sufficient controls been established toprevent the exposure of non-beta-lactam drug products tocross-contamination. In addition, containment procedures have notbeen established to assure that employees, in moving about theplant, do not carry residue from penicillin/non-penicillinbeta-lactams into nonpenicillin areas. This separation (penicillinroom) is ineffectual given the lack of containment procedures andpractices observed by the investigator. For example, employees areallowed to repack non-penicillin and non-beta-lactam drug productsafter re-packing penicillin and/or non-penicillin beta-lactam drugproducts; employees do not change work apparel between packingpenicillin drug products and non-penicillin drug products; employeesmove throughout the facility without restriction and share commonareas, such as cafeterias and restrooms without re-gowning.

Failure to separate completely the air handling systems for thepacking of penicillin products and non-penicillin beta-lactam drugproducts from non-penicillin drug products. [21 CFR 211.42(c) and211.46(d)]

The same air handling system is used for the repackaging ofpenicillin and cephalosporins in violation of 21 CFR 211.42(c) and(d).

There is a failure to develop control systems for your operationas are necessary to prevent contamination of the aseptic processing,which includes a system for monitoring environmental conditions. [21CFR 211.42(c)(10)(iv)]

No evaluation has been performed to show the adequacy andefficacy of the cleaning and disinfection process used in parenteralfilling room […] as specified by SOP […] [21 CFR211.42(c)(10)(v)].

Investigations of a batch failure or any of its componentsprocessed in the aseptic processing area did not extend to otherdrug products that may have been associated with a specific failureor discrepancy. The heat exchanger used in the Small VolumeParenteral manufacturing rooms […] was found to be contaminatingthe water for injection (WFI) with bacteria. The failureinvestigation did not extend to reviewing the possible impact onother previously manufactured drug products. In addition, the heatexchanger continued to be used to manufacture other parenteralproducts 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 beflushed or rewetted. [21 CFR 211.192 and 21 CFR211.42(c)(10)(vi)]

Failure to perform operations within separate or defined areas orto use other control systems as are necessary to preventcontamination or mix-ups [21 CFR 211.42(c)].

For example, cans of a raw material labeled as "BenzylPeroxide" being held pending sampling and testing were observedoutside of the quarantine area on the same shelf as lots of the samematerial that had been released for use (21 CFR 211.42(c)(1)). Inaddition, barrels of rejected […] were stored in the QA releasedraw materials storage area (21 CFR 211.42(c)(2))

The flow of drug product containers, closures, and drug productsthrough the building is not designed to prevent contamination (21CFR 211.42(b)).

Specifically: Sterilized glassware (including mixing beakers andproduct vials), containers of sterilized product, and bags ofsterilized stoppers are carried through the unclassified workroomand the class 10,000 compounding room in order to get them into thefilling room. The hot air ovens and autoclaves do not open into thefilling room.

Control systems for monitoring environmental conditions duringaseptic processing operations are inadequate (21 CFR211.42(c)(10)(iv).

Specifically: Environmental monitoring for filling operationsdoes not include the operator's gown and gloves.

Failure to have control systems necessary to preventcontamination during the course of aseptic processing operations,including an air supply filtered through high-efficiency particulateair […] filters under positive pressure [21 CFR211.42(c)(10)(iii)].

Themanufacture of your ophthalmic drug products is not conducted in acontrolled room environment or under appropriate […] filtered airsupply necessary to prevent contamination.

Your firm failed to establish a system for monitoringenvironmental conditions in the aseptic, processing area as requiredby 21 CFR 211.42(c)(10)(iv).

Specifically,routine environmental monitoring of the aseptic filling area forviable and non-viable particulates is not done. Routinemicrobiological monitoring of the gowns and gloves of the employeesworking in the class 100 area is not done. [Reference: Form FDA 483,Observation 4]

Harald Martin
CONCEPT Heidelberg



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