Preventing Metal Contamination
Preventing Metal Contamination
Preventing Metal Contamination
INTRODUCTION
How does one manage the apparent conflict between
the regulatory and safety goals of zero tolerance for
pharmaceutical product metal contamination when
most manufacturing equipment is constructed of
metal? Is it even possible to completely prevent the
presence of minute quantities of metal in our products? Product contamination with metal particles is
unacceptable from both regulatory and safety perspectives. So, how do we address this challenge?
It is essential that any metal contamination management approach be comprehensive. One simply
cannot rely alone on removal of rogue contaminants
or safety screening of raw materials. This discussion
aims to outline an approach to metal contamination
prevention that should achieve a level of control acceptable to all stakeholders. A three-tiered approach
to prevent metal contamination is described. The approach includes the following:
Prevention measures as a key means for avoiding contamination
Application of in-process controls to remove
the presence of metal particles
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manufactured. Does this, in itself, constitute adulteration? At what point does routine, normal wear become a concern? How do you know if missing metal
was worn away as micro-dust versus a single piece?
No one would question that bolts, nuts, etc., imparted
to products would be unacceptable, but what about
the micro-dust?
It appears that most in industry and FDA have come
to accept the presence of visible particulate contamination as the limit for acceptable versus unacceptable
contamination. Most individuals with normal vision
can detect a particulate in the range of 4050 micrometers in size. FDA clarified this limit in a 2002
Warning Letter issued to Berlex Pharmaceuticals:
While it is generally understood in the pharmaceutical industry that normal wear and tear of manufacturing equipment may lend particulate matter to
the products being produced, this type of particulate
matter is not visible to the naked eye and is in the
parts per million (ppm) or parts per billion (ppb)
range. It is not acceptable to have visually observable
contaminants in your finished dosage form (6).
The bottom line for industry is to prevent the presence of those visible particles in the finished drug
product.
THREE-TIERED APPROACH
TO PREVENTION OF METAL CONTAMINATION
Any comprehensive approach to prevention of metal
contamination in drug products requires a threetiered approach, as follows:
Prevention
Removal
Detection.
Examples of each activity can be seen in the Table.
Prevention
Preventing the introduction of visible metal particles
into the process is the best approach to ensuring acceptable product. There are several key preventive activities that should be considered in a comprehensive
approach, as follows:
Design for qualitythe use of intentional
actions to design the equipment or process to
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Examples
PREVENTION
1. Design for Quality
2. Preventive maintenance
Tack-weldorotherwisesecurebolts,nuts,andotherinternalparts
Processdesignedforclosedversusopendryingsystems(e.g.,rotary
dryer instead of tray drying)
Limitationsontypes,numbers,anduseofmaintenancetoolsand
equipment (e.g., documented retrieval after maintenance)
Properly-designedfacilitiestorequiretransitionareasforpeopleand
material flow
EnhancedfrequencyofPMformovingpartsorpotentialsourcesof
contamination (see FMEA below)
EnhancedPMrigortoincludemeasurementofwear,photographs,etc.
E/P
3. Preventionofmetal-to-metalcontact Useofnon-stickplasticorothernon-metalmaterialswhenpossible
4. Barriers
Pre-manufacturingcampaigninspectionofmovingpartsforwear
ConductextensiveFMEAtoidentifypotentialsourcesofcontamination
1. In-line filters
2. In-line magnets
Useofmetaldetectionsystemsinbulkhandlingortabletcompression
DETECTION
3. Statistically-basedproductinspection Useofelectronicvisionsystemsforproductinspectionorhuman
inspection as an element of final product release
(a) P = procedural control; E = engineering control
E/P
In-line filtersthe use of filters to protect solutions is well established. A formal review of the
process to identify any new opportunities for
filters or safety screens can often pay dividends.
It is not unusual that issues occur after the final
filtration or screening that can result in product
contamination. So examine systems as close to
the final packaging as possible.
In-line magnetssimilarly, in-line magnets
are effective in removing rogue metal particles.
Though stainless steel is typically not conductive
to magnets, very small particles are often electrically charged, making them susceptible to earth
magnets.
Detection
When prevention and removal activities have failed
to effectively eliminate foreign metal contamination
from product, systems for detection are typically employed as a final protection against adulterated product, as follows:
Metal detection systemsthe use of metal detection systems is broadly accepted as effective for
many manufacturing systems. However, the
effectiveness of these systems is dependent upon
the following key factors:
Quality of the system purchasedsystems
vary significantly in sensitivity, speed of detection, and overall reliability.
Aperture sizethe ability of the system to
detect a metal particle is a function of the system aperture size or proximity of the system to
product; as an example, because the aperture
size for tableting operations is smaller than
that available for bulk powders, the tableting
system can detect a particle 10x smaller than
can a bulk system.
Flow ratethe higher the flow rate, typically,
the lower the detection sensitivity.
Material compositionsome materials limit
the system sensitivity. Additionally, the type
of metal involved can impact the sensitivity of
the system. For example, ferrous metal is much
more sensitive to detection than stainless steel.
Automatic diverter systemsthe use of a prod-
ENGINEERING CONTROLS
VERSUS PROCEDURAL CONTROLS
Two types of controlsengineering and proceduralare typically used in a comprehensive approach
to elimination of metal contamination in pharmaceutical products. Engineering controls are those built
into the equipment, system, or processes not directly
dependent upon human interaction for success. Examples include mechanical devices, environmental
controls, or computer systems. Certainly, we must
include appropriate validation and qualification of
these controls to ensure they are adequate and properly function. When done well, engineering controls
can typically be relied upon to provide greater and
more consistent performance than controls relying
upon personnel performance.
Procedural controls are human based and dependent upon individuals properly performing tasks
defined in standard operating procedures, batch records, work instructions, or other controlled documents. Some of the keys for successful procedural
controls include a clear and understandable procedure, effective training, and motivated employees
following procedures with discipline.
Engineering controls cannot be applied to every
manufacturing activity. However, processes can be
perfected to the extent possible. The use of colorcoding, poke yoke practices, and applicable verification systems can minimize non-adherence.
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CONCLUSIONS
The control and prevention of metal contamination in
pharmaceutical products is a challenge from all perspectivesregulatory, safety, and manufacturing. It is clear
that visible metal particles are unacceptable. Control of
metal contamination cannot be readily achieved with
a single-pronged approach. We must employ a multifaceted, comprehensive approach to ensure a sustainable performance for prevention of metal contamination. This approach must include intentional prevention
activities, in-process control or removal and, ultimately,
detection as a final safety net. Any approach that does
not include all three facets will likely yield unacceptable
results over the long term. It is also important to understandthatbothengineeringandproceduralcontrols
must be employed along with formal oversight (e.g.,
validation, qualification, training, verification, effectiveness, and documentation).
By enhancing our overall control strategy to include
thiscomprehensiveapproach,weshouldexpectsuccess
in the control of metal contamination of our products.
REFERENCES
1. FDA, 21CFR211.67, (a) Equipment, cleaning, and maintenance, 43 Federal Register 45077, Sept. 29, 1978, as amended at
73 FR 51931, Sept. 8, 2008.
2. FDA, 21CFR211.84, 43 Federal Register 45077, Sept. 29, 1978,
as amended at 63 FR 14356, Mar. 25, 1998; 73 FR 51932, Sept.
8, 2008.
3. ICH, Q7, Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, November 2000.
4. FDA, Compliance Program Guidance Manual, CPGM 7356.002,
US Food and Drug Administration.
5. USP, Chapters <1> <788>, <797>, United States Pharmacopeia/
National Formulary.
6. FDA, Warning letter to Berlex Laboratories, March 11, 2002.
http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2002/ucm144810.htm accessed 12/329/11. GXP
Lorraine Mercurio is a project manager in the Product Development organization of Covidien in St. Louis, Missouri, where she
manages a wide variety of pharmaceutical development projects.
She has previously served in a number of quality-related roles
in the pharmaceutical industry, at such companies as Covidien,
KV Pharmaceutical, and Sanofi-Aventis. She holds a Bachelors
of Arts in biology from the University of Missouri-St. Louis and a
Masters of Arts in quality management from Webster University
in St. Louis, Missouri. Lori can be reached at lorraine.mercurio@
covidien.com.
Eldon Henson is Director, Operations Technical Services at
Covidien in St. Louis, Missouri and serves as President-elect of
the Missouri Valley Chapter of the Parenteral Drug Association.
Eldon may be reached by e-mail at [email protected]
or [email protected].