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4.1 Equipment Design and Placement
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.
What is the significance of defects in container-closure integrity of an injectable? Can product sterility be affected?
References:
211.63 Equipment design, size, and location;
211.110 Written procedures; deviations;
211.186 Master production and control records;
211.192 Production record review
A number of injectable pharmaceuticals have been voluntarily recalled over the last two years due to critical defects in container-closure systems. These product integrity problems included glass fractures or leaks. Product non-sterility was one of the consequences of these defects.
In the case of most recalls, investigations were not conducted in accord with 21 CFR 211.192. In some instances, while the cause of the defects was known, corrective actions were not implemented and impact on past and future batches was not determined. As a result, new lots were produced with the same serious quality problem, the defective product was shipped, and health practitioners began registering complaints with FDA and the manufacturers.
The critical defects stemmed from various causes. Rough or irregular handling during specific process steps was a common denominator in each of the recalls. Some specific examples of causes include:
 | Deficient capping/sealing station design resulted in excessive stress to the vial neck. |
| Rough transfer mechanism exerted excessive force on containers while being conveyed down the processing line. |
| Lyophilizer operation included rough loading or stoppering step. |
| Container-closure system could not withstand autoclave process. |
| Vial washer was not compatible with the dimensions/durability of a new container. The new vial size did not adequately fit with the guides in the washer and caused chips in the vial neck. |
We have seen several other scenarios in which process deficiencies lead to loss of vial, ampul, or cartridge integrity. But mechanical problems have not been the only cause identified. Investigations have also attributed problems to improper manual handling. Trays dropped by personnel after final packaging, and rough charging of vials to the processing line, have resulted in recalls. In the former case, vial integrity was lost and the product was subsequently found to be non-sterile. Contaminated water from a washing step performed by the firm after autoclaving was named as the source of the predominant water-borne bacterium contaminating the vials.
Just as the container-closure system chosen by a firm needs to be a robust one to ensure sterility and stability, there
must also be compatibility with the production line on which the product will be manufactured. As cited above,
incompatibility of a new container-closure with an existing line has resulted in loss of integrity. FDA requires firms to
develop consistent processes employing suitable manufacturing equipment (see 211.65 and
211.100). This equipment should be qualified to process product in a manner that assures integrity of the specific container-closure.
As a final measure, a batch manufacturing operation includes an inspection stage intended to reject defective units. It is important to be mindful that final visual/electronic inspection has its limitations. In particular, the nature (e.g., location, visibility) of a given defect may make its detection problematic. Some critical defects are difficult or impossible (e.g., hidden cracks under the crimp, etc.) to detect during the final inspection stage. This fact underscores the importance of building quality into a manufacturing operation to prevent serious defects. For each batch of a parenteral drug product, reconciliation records should document the actual quantities of defective units detected, categorized by major defect type. These results should be compared to established specifications, and an investigation triggered if results are beyond specifications. In addition, upon detection, a critical defect should be investigated. A lot should not be released for shipment in the event that it contains units lacking container-closure integrity.
Contact for further information:
Richard L. Friedman, HFD-325; phone: (301) 594-0098;
e-mail: friedmanr@cder.fda.gov
Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 8, Number 2) June, 2000
This same text is also reprinted in Framework sections 4.5
and 7.2.
Does FDA approve materials of construction for equipment? For example, are there any specific CGMP requirements regarding ferrite content and other properties of 316L stainless steel used in storage tanks for pharmaceutical water systems?
Reference:
21 CFR Sections 211.63, Equipment design, size, and location,
211.72, Filters,
211.65, Equipment construction,
211.67, Equipment cleaning and maintenance, and
211.48, Plumbing;
Guide To Inspections Of High Purity Water Systems, July,
1993.
FDA does not approve or prohibit specific equipment or materials (with rare exceptions such as the requirements relating to asbestos filters found at 21 CFR 211.72). A storage tank or other piece of equipment is subject to the general CGMP requirements addressing equipment suitability. For example, section 211.65 requires surfaces that contact components, in-process materials, or drug products not be reactive, additive, or absorptive so as to adversely affect product quality. Section 211.63 requires that equipment be of appropriate design to facilitate operations for its intended use and for cleaning and maintenance. Section 211.67 requires firms to clean, maintain, and sanitize equipment at appropriate intervals to prevent malfunctions or contamination that would adversely affect product quality.
To illustrate, it's important that interior surfaces of a sanitary storage tank are capable of being cleaned, sanitized, and (if needed) sterilized. For such sanitary equipment, design provisions to prevent backsiphonage (see Section 211.48) and stagnation are among the attributes that prevent microbial contamination of a drug product. Likewise, smooth interior surfaces (e.g., welds) help prevent collection of microbial contamination and formation of a biofilm. (See the above inspection guide for more information on biofilms.)
So choosing materials or components for any equipment involves evaluating whether there is any potential for an adverse impact on drug product quality. In this respect, various compatibility considerations (e.g., leachables, interaction with formulations/sanitizers, ability of material to withstand sterilization) can often take on the most CGMP significance.
Ultimately, provided that such CGMP requirements are met, firms are afforded the flexibility to select the material and grade which best satisfies the needs of their particular application. Given this information, it should be no surprise that the CGMP regulations do not include specifics on what ferrite content is appropriate in stainless steel. However, a number of references may provide a useful starting point when researching issues such as sanitary design standards, surface grit/smoothness, pits, folds, crevices, and steel composition (including ferrite content). The milk industry has publications (e.g., "3-A Accepted Practices for Permanently Installed Sanitary Product Pipelines and Cleaning Systems") written jointly with the U.S. Public Health Service regarding sanitary design. ANSI (American National Standards Institute) also publishes documents addressing design of seamless and sanitary piping. Such literature should be available through a search on the American Iron and Steel Institute (1000 16th Street, N.W., Washington, D.C. 20036) website at www.steel.org. A search on words such as "seamless" and "weld" at www.nssn.org will yield further relevant references.
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
7, Number 3) September, 1999.
This same text is also reprinted in Framework section 4.3.
