Peer R e v i e w ed: Q uali t y Co n t r o l

Developing a Comprehensive Approach

for Preventing Metal Contamination of
Pharmaceutical Products
Lorraine Mercurio and Eldon Henson

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 is described. This paper also discusses the
application of engineering and procedural controls in
pharmaceutical manufacturing. Practical examples to
cover a variety of pharmaceutical dosage forms are
included to illustrate this comprehensive approach.

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

Systems for detection of metal contamination

and monitoring controls.
This paper also discusses the application of engineering and procedural controls in pharmaceutical
manufacturing. Practical examples to cover a variety
of pharmaceutical dosage forms are included to illustrate this comprehensive approach.
REGULATORY BASIS FOR
ZERO TOLERANCE ON METAL CONTAMINATION
The regulatory requirement to control manufacturing processes to avoid contamination with extraneous materials is clear. In Chapter 21 of the Code of
Federal Regulations Section 211.67 (a) under Equipment, cleaning, and maintenance, the following is
observed:
Equipment and utensils shall be cleaned, maintained, and, as appropriate for the nature of the drug,
sanitized and/or sterilized at appropriate intervals to
prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of
the drug product (1)
In Chapter 21 of the Code of Federal Regulations
Section 211.84 (d)(5), the following is included under Testing and approval or rejection of components,
drug product containers and closures:
Each lot of a component that is liable to contamination with filth, insect infestation, or other extraneous adulterant shall be examined against established
specifications for such contamination (2).
For active pharmaceutical ingredient (API) manufacturing, International Conference on Harmonisation (ICH) Q7 V. A. (5.1) states:
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Peer Reviewed: Qualit y Control

Closed or contained equipment should be used

whenever appropriate. Where open equipment is
used, or equipment is opened, appropriate precautions should be taken to minimize the risk of contamination (3).
Additionally, the US Food and Drug Administrations Compliance Program Guidance Manual (CPGM
7356.002), the manual used to direct facilities inspections by FDA, lists controls to prevent contamination as an element of the inspections for facilities and
equipment systems (4).
Many firms have been cited in FDA-483 observations or warning letters for failing to prevent the
contamination of drug products with foreign material. These citations have impacted oral solid dosage
products, parenterals, and nearly every other product
type. The bottom line expectation for industry is that
current good manufacturing practices (CGMP) and all
associated guidance documents require that all necessary measures be applied to ensure contamination is
prevented. These measures include the following:
Control or inspection of raw materials and packaging components
Protection of exposed product
Proper selection and maintenance of equipment
Cleaning of equipment
Proper facility and flow design
Precautions during product sampling and testing
Proper storage and shipment of drug products.
Failure to prevent product contamination renders affected product adulterated under the Food,
Drug and Cosmetics Act. The bar is high regarding
product protection. There is no allowed tolerance for
product contamination, and systems must be established to prevent it.
SAFETY CONCERNS FOR METAL CONTAMINATION
The primary reason for zero tolerance of unplanned
contamination by foreign materials relates to consumer safety. Particulates in parenteral products, for
example, can block capillaries and, under worst-case
conditions, could result in death. Metal particulates in
oral solutions or solid dosage products could potentially damage teeth if chewed, abrade internal organs,
52 Journal of GXP Compliance

or pose toxicological concerns.

Most pharmaceutical manufacturing equipment is
constructed of stainless steel. This can vary in composition; in general, it is comprised of chromium, nickel,
zinc, or manganese. Minute levels of ingestion are not
expected to pose adverse health consequences.
Nonetheless, the mere potential for adverse health
or safety impacts from foreign contamination elevates
the concern. And foreign contamination of unknown
size, composition, or toxicity actually poses a risk
greater than that for known materials.
INDUSTRY PERSPECTIVES
ON METAL CONTAMINATION
FDA has not established formal limits for foreign
material contamination in drug products other than
those listed in the United States Pharmacopeia (USP),
as follows:
USP <1>Injections: All articles intended for
parenteral administration shall be prepared in a
manner designed to exclude particulate matter
and other foreign matter. Units with visible particulates shall be rejected.
USP <788>Particulate Matter in Injections:
The average number of particles present cannot
exceed 3000 per container equal to or greater
than 10 micrometers in size and 300 particles
per container equal to or greater than 25
micrometers.
USP <797>Pharmaceutical Compounding Sterile Preparations: All units must be inspected
and rejected when visible particulate matter is
detected (5).
The challenge is to control contamination, not to a
limit or specification, but to a level often deemed as
the absence of visible contamination.
Stainless steel equipment will eventually wear. For
example, table press tooling must be inspected frequently for adverse wear or pitting. Critical tooling
is required to be dimensionally evaluated regularly
to ascertain if it is still in tolerance. Blenders, agitators, mills, and other moving parts are also known to
show wear over time. Where does this missing metal
go? Some of it may be imparted to the product being

Lorraine Mercurio and Eldon Henson

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

eliminate potential sources of metal contamination. This proactive approach to product or

process design should include the use of specific
risk assessment tools. By using proper design,
future issues can be avoided.
Preventive maintenance (PM)issues with
metal contamination can often be traced to
inadequate PM or excessive intervals between
PM. Increasing the frequency and rigor of PM
for high-risk equipment (e.g., that with moving
parts or in direct contact with product) can often
reduce contamination potential.
Prevention of metal-to-metal contactthere are
alternatives to metal parts and, whenever possible, these should be used in high-risk areas.
Barriersthe use of proper barriers can reduce
or eliminate the potential for contamination with
metal and other foreign matter. Work toward
closed systems wherever possible and consider
constructing other barriers (such as transparent
thermoplastic boxes or shields) when open systems cannot be avoided.
Extensive cleaning and inspectionproper
equipment cleaning and inspection cannot be
overstated. By ensuring careful inspection with
appropriate documentation (e.g., measurements
and photographs), you can more readily identify
excessive or unacceptable wear on equipment.
The use of infrared (IR) analysis or vibratory
evaluation tools can also help predict the potential for catastrophic equipment failure.
Quality risk assessmentthe use of a formal,
documented process to identify all potential
sources of metal contamination and the risk
each poses is an essential element to a comprehensive and proactive prevention approach. A
failure mode and effects analysis (FMEA) can
ultimately identify every potential failure, guiding you to an acceptance of the risk posed or
reduction or elimination of that risk.
Removal
The following two primary methods are employed to
effectively remove metal particles from product during manufacturing:
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Table: Summary of metal contamination control activities with example applications.

Control Method

Examples

Control Type (a)

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

Facilitydesignstoincludeproperheating/ventilation/airconditioning (HVAC), materials of construction and cleanability

EnhancedfrequencyofPMformovingpartsorpotentialsourcesof
contamination (see FMEA below)

EnhancedPMrigortoincludemeasurementofwear,photographs,etc.

Utilize IR, vibratory analysis or other contemporary equipment

inspection processes to identify early signs of failure

E/P

3. Preventionofmetal-to-metalcontact Useofnon-stickplasticorothernon-metalmaterialswhenpossible
4. Barriers

Use plastic or Teflon sampling devices

Closed manufacturing systems

Closure of open systems using constructed barriers

5. Extensive cleaning and inspection Routineinspectionofmillorsifterscreens(e.g.,severaltimes/day)

Pre-manufacturingcampaigninspectionofmovingpartsforwear

ConductextensiveFMEAtoidentifypotentialsourcesofcontamination

1. In-line filters

Safety screens, particulate filters, etc.

2. In-line magnets

Use of earth magnets in bulk handling

1. Metal detection systems

Useofmetaldetectionsystemsinbulkhandlingortabletcompression

2. Automatic diverter systems

Automated diversion of product upon detection of metal

6. Quality risk assessment

REMOVAL

DETECTION

3. Statistically-basedproductinspection Useofelectronicvisionsystemsforproductinspectionorhuman
inspection as an element of final product release
(a) P = procedural control; E = engineering control

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E/P

Lorraine Mercurio and Eldon Henson

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.

uct diversion system in conjunction with metal

detection systems will help ensure product
protection is comprehensive. The use of manual
diversion or product segregation can be ineffective if not perfectly executed.
Statistically-based product inspectionfinally,
the entire approach described above must be
supplemented with some level of statisticallybased product inspection. Full, 100% inspection
is not advocated, but some risk-based inspection
that can truly help identify concerns is key. The
use of ongoing monitoring or statistical process
controls can identify adverse trends or support
the PM program.

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

56 Journal of GXP Compliance

ARTICLE ACRONYM LISTING

API Active Pharmaceutical Ingredient
FDA US Food and Drug Administration
PM
Preventive Maintenance
USP United States Pharmacopeia

ABOUT THE AUTHORS

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 eldon.henson@covidien.com
or henson333@hotmail.com.