FDA Findings During Inspections on Design and Construction of Equipment

GMP News No. 525

GMP News
7 March 2005

FDA Findings During Inspections
on Design and Construction of Equipment

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.

Do 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".

Original Wording

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

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 211.46(d)]

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

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 CFR 211.42(c)(10)(iv)]

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 211.42(c)(10)(v)].

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 211.42(c)(10)(vi)]

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 CFR 211.42(b)).

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 filling room.

Control systems for monitoring environmental conditions during aseptic processing operations are inadequate (21 CFR 211.42(c)(10)(iv).

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 air […] filters under positive pressure [21 CFR 211.42(c)(10)(iii)].

The 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, Observation 4]

Harald Martin
CONCEPT Heidelberg


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