3.3 Facility Maintenance and Good Housekeeping Program

This page will address various regulatory issues related to this section of the GMP Institute framework.  Click below to view the issues that are relevant to you.

Are firms required to use HEPA filters in the manufacture of tablets and capsules?

Is nonviable particulate monitoring under static rather than dynamic conditions acceptable for routine monitoring of aseptic processing areas?

Is there an acceptable substitute for DOP to integrity test HEPA filters?

Would FDA disapprove a pharmaceutical plant because it was located next to a landfill site?

Are firms required to use HEPA filters in the manufacture of tablets and capsules?

References: 
21 CFR 211.46, Ventilation, air filtration, air heating and cooling; 
211.42, Design and construction features

No. The CGMP regulations do not specifically require tablet and capsule manufacturing facilities to maintain high-efficiency particulate air (HEPA) filtered air. The regulations, at 211.46, do require use of equipment for adequate control over air pressure, microorganism, dust, humidity and temperature when appropriate. In addition, this section calls for use of air filtration systems, including prefilters and particulate matter air filters on air supplies to production areas, as appropriate. These provisions speak to measures to prevent cross contamination, and the key phrase is "as appropriate".

Do not confuse the 211.46 provisions with 211.42(c)(10)(iii) which calls for aseptic processing areas to be equipped, as appropriate, with an air supply filtered through HEPA filters. Whereas such filtration is the norm for aseptic areas, tablet and capsule production rooms seldom need the same level of air filtration.

Despite the lack of an explicit CGMP requirement, some firms may elect to use HEPA filtered air systems as part of their dust control procedures. For example, firms may perform dust containment assessments and decide that such filters are warranted to prevent cross contamination of highly potent drugs that, even in small quantities, could pose a significant health hazard when carried over into other products.

Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 5, Number 3) September, 1997.
This text is also reprinted in framework section 3.2.

Is nonviable particulate monitoring under static rather than dynamic conditions acceptable for routine monitoring of aseptic processing areas?

References: 
21 CFR 211.160(b), General requirements (Subpart I Laboratory Controls); 
211.113, Control of microbiological contamination; 
1987 Guideline on Sterile Drug Products Produced by Aseptic Processing.

No. Sampling an environment for particulates during static (at rest) times is of minimal utility in assessing actual processing conditions. On the other hand, operational (dynamic) monitoring performed throughout aseptic processing is needed. Here's why.

Aseptic processing operations are designed to exclude living microorganisms, endotoxins, and particulates from the finished product. It is generally accepted that monitoring of particulate concentration in classified (environmentally controlled) areas during operations serves as a direct indicator of changes in local air quality while indirectly indicating the increased potential for the introduction of microorganisms to the monitored area.

Occasional static monitoring during periods of no operation to ensure particulate levels remain well below an area's classification level would be useful as a facility maintenance parameter. However, firms should obtain data from dynamic monitoring (during operations) as a routine batch control. Firms should monitor frequently throughout manufacturing, and in proximity to the work surfaces and exposed product or container/closures. For example, in class 100 areas, samples should be taken about one foot away from the work surface. Many firms now have the capability to monitor nonviables continuously; however, failure to monitor continuously is not objectionable.

High levels of particulates generally represent a departure from processing norms, indicating, for example, unusual personnel activity which challenges the intended cleanroom design parameters. It is therefore important that the Quality Control unit investigate such "particulate excursions."

Finally, when qualifying a cleanroom, firms conduct studies to establish the room's air classification. Although the classification studies include assessment of particulate levels under static conditions, the final classification should be derived from data generated while equipment is in place and operations are ongoing.

Contact for further information: Richard L. Friedman, HFD-322, 301-594-0095; e-mail: friedmanr@cder.fda.gov

Reprinted from FDA's Human Drug CGMP Notes, (Volume 5 Number 2), June, 1997.
This text is also reprinted in Framework section 3.2.

Is there an acceptable substitute for DOP to integrity test HEPA filters?

Reference: 
21 CFR 211.46, Ventilation, air filtration, air heating and cooling, and
211.67 Equipment cleaning and maintenance.

Yes. Dioctyl phthalate aerosols also called Di (2-ethylexyl) phthalate, di-sec octyl phthalate, DOP, or DEHP, have long been used to test the integrity of high efficiency particulate air (HEPA) filters. Concern about the potential health effects to people working with DOP test aerosols has led to a search for a safer equivalent replacement.

The prime candidate from U.S. Army testing with assistance from various private companies was a Henkel Corporation (Emery Group) product called Emery 3004 PAO. This product is a polyalphaoefin (POA) in the 4 centistoke (4 cSt) viscosity grade, used primarily as a lubricant base stock for oils, lubricants, and electrical/hydraulic fluids.

As cited in the March 1994 Human Drug CGMP Notes, based on data submitted to FDA we have concluded that Emery 3004 (POA) can replace DOP in HEPA integrity testing.

The original manufacturing site which produced the Emery 3004 (POA) for the data submitted has changed since the study and Emery 3004 (POA) is now manufactured at a different site. Discussions with the Army and the companies involved in the original studies indicate the product remains the same from the new site of manufacturing. CDER has also compared the original specifications and the new site specifications along with data from the Material Safety Data Sheets and agrees that there is no significant difference in the product from either site.

The Chemical Abstracts Service (CAS) number which identifies this product also remained as 68649-12-7.

Other reported alternatives used in the industry include DOS ( Di (2-ethylhexyl) sebacate ) and Ondina Oil. However, no manufacturer has yet submitted all the necessary data to evaluate these alternatives.

As such, Emery 3004 POA with the CAS number 68649-12-7 still remains an acceptable replacement for DOP.

Contact for further information: Michael J. Verdi, HFD-322, 301-594-0095; e-mail: verdim@cder.fda.gov

Reprinted from FDA's Human Drug CGMP Notes, (Volume 4 Number 4), December, 1996.

Would FDA disapprove a pharmaceutical plant because it was located next to a landfill site?

Reference: 
21 CFR Part 211, Subpart C, Buildings and Facilities, generally.

Not necessarily. More important than a facility's proximity to sources of contamination is the adequacy of measures the firm takes to prevent such contamination from adversely affecting drug product quality. It would be far from prudent to locate a pharmaceutical establishment alongside a land reclamation facility (which conjures up visions of such potential sources of contamination as rodents, insects, birds, and ground water toxic leachates). The task of protecting the drug product and production environment from such contamination would be challenging, but not insurmountable. Field investigators who encounter such a situation should, of course, pay close attention to how the firm isolates production operations from potential contaminants. However, in the absence of demonstrated routes of contamination, we would not disapprove of the facility based solely on its proximity to the landfill.

Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 3, Number 1) March, 1995.
This text is also reprinted in Framework section 3.2 .