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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 Howdoesonemanagetheapparentconflictbetween 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 prod- ucts? Product contamination with metal particles is unacceptable from both regulatory and safety per- spectives. So, how do we address this challenge? it is essential that any metal contamination man- agement 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 ac- ceptable to all stakeholders. a three-tiered approach to prevent metal contamination is described. the ap- proach includes the following:

• Prevention measures as a key means for avoid- ing 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 engi- neering and procedural controls in pharmaceutical manufacturing. Practical examples to cover a variety of pharmaceutical dosage forms are included to illus- trate this comprehensive approach.

reGulatory BaSiS For Zero toleraNCe oN Metal CoNtaMiNatioN the regulatory requirement to control manufactur- ing processes to avoid contamination with extrane- ous materials is clear. in Chapter 21 of the Code of Federal regulations Section 211.67 (a) under “equip- ment, cleaning, and maintenance,” the following is observed:

“equipment and utensils shall be cleaned, main- tained, and, as appropriate for the nature of the drug,

sanitized and/or sterilized at appropriate intervals to

preventmalfunctionsorcontaminationthatwouldal-

ter 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 un- der“testingandapprovalorrejectionofcomponents, drug product containers and closures:” “each lot of a component… that is liable to contam- ination with filth, insect infestation, or other extrane- ous adulterant shall be examined against established specifications for such contamination” (2). For active pharmaceutical ingredient (aPi) manu- facturing, international Conference on Harmonisa- tion (iCH) Q7 V. a. (5.1) states:

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“Closed or contained equipment should be used whenever appropriate. Where open equipment is used, or equipment is opened, appropriate precau- tions should be taken to minimize the risk of con- tamination” (3). additionally, the uS Food and drug administra- tion’s Compliance Program Guidance Manual (CPGM 7356.002), the manual used to direct facilities inspec- tions by Fda, lists “controls to prevent contamina- tion” as an element of the inspections for facilities and equipment systems (4). Many firms have been cited in Fda-483 obser- vations or warning letters for failing to prevent the contamination of drug products with foreign mate- rial. these citations have impacted oral solid dosage products,parenterals,andnearlyeveryotherproduct type. the bottom line expectation for industry is that current good manufacturing practices (CGMP) and all

associatedguidancedocumentsrequirethatallneces-

sary measures be applied to ensure contamination is prevented. these measures include the following:

• Control or inspection of raw materials and pack- aging 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 ren- ders 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 estab- lished to prevent it.

SaFety CoNCerNS For Metal CoNtaMiNatioN the primary reason for zero tolerance of unplanned contamination by foreign materials relates to con- sumer 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 poten- tially damage teeth if chewed, abrade internal organs,

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or pose toxicological concerns. Most pharmaceutical manufacturing equipment is constructed of stainless steel. this can vary in compo- sition; 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 orsafetyimpactsfromforeigncontaminationelevates 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 par- ticulates 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 Ster- ile 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 fre- quently for adverse wear or pitting. Critical tooling is required to be dimensionally evaluated regularly to ascertain if it is still “in tolerance.” Blenders, agita- tors, 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

manufactured. does this, in itself, constitute adultera- tion? at what point does routine, normal wear be- come 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 contami- nation as the limit for acceptable versus unacceptable contamination. Most individuals with normal vision can detect a particulate in the range of 40–50 mi- crometers in size. Fda clarified this “limit” in a 2002 Warning letter issued to Berlex Pharmaceuticals:

“While it is generally understood in the pharma- ceutical industry that normal wear and tear of manu- facturing 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 pres- ence 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 three- tiered 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 ac- ceptable product. there are several key preventive ac- tivities that should be considered in a comprehensive approach, as follows:

• design for quality—the use of intentional actions to design the equipment or process to

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eliminate potential sources of metal contami- nation. 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 contact—there are alternatives to metal parts and, whenever pos- sible, these should be used in high-risk areas.

• Barriers—the 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 sys- tems cannot be avoided.

• extensive cleaning and inspection—proper 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 poten- tial for catastrophic equipment failure.

• Quality risk assessment—the 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 compre- hensive and proactive prevention approach. a failure mode and effects analysis (FMea) can ultimately identify every potential failure, guid- ing 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 dur- ing 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

 

tack-weldorotherwisesecurebolts,nuts,andotherinternalparts

e

 

Processdesignedforclosedversusopendryingsystems(e.g.,rotary dryer instead of tray drying)

e

limitationsontypes,numbers,anduseofmaintenancetoolsand equipment (e.g., documented retrieval after maintenance)

P

Properly-designedfacilitiestorequiretransitionareasforpeopleand material flow

e

Facilitydesignstoincludeproperheating/ventilation/aircondition-

e

ing (HVaC), materials of construction and cleanability

2. Preventive maintenance

 

enhancedfrequencyofPMformovingpartsorpotentialsourcesof contamination (see FMea below)

P

 

enhancedPMrigortoincludemeasurementofwear,photographs,etc.

P

utilizeir,vibratoryanalysisorothercontemporaryequipment inspection processes to identify early signs of failure

e/P

3.Preventionofmetal-to-metalcontact

useofnon-stickplasticorothernon-metalmaterialswhenpossible

e

use plastic or teflon sampling devices

e

4. Barriers

 

Closed manufacturing systems

e

 

Closure of “open” systems using constructed barriers

e

5. extensive cleaning and inspection

routineinspectionofmillorsifterscreens(e.g.,severaltimes/day)

P

Pre-manufacturingcampaigninspectionofmovingpartsforwear

P

6. Quality risk assessment

 

ConductextensiveFMeatoidentifypotentialsourcesofcontamination

P

reMoVal

 

1. in-line filters

 

Safety screens, particulate filters, etc.

e

2. in-line magnets

 

use of earth magnets in bulk handling

e

deteCtioN

 

1. Metal detection systems

 

useofmetaldetectionsystemsinbulkhandlingortabletcompression

e

2. automatic diverter systems

 

automated diversion of product upon detection of metal

e

3.Statistically-basedproductinspection

useofelectronicvisionsystemsforproductinspectionorhuman inspection as an element of final product release

e/P

(a) P = procedural control; e = engineering control

 

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• in-line filters—the use of filters to protect solu- tions 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 magnets—similarly, in-line magnets are effective in removing rogue metal particles. though stainless steel is typically not conductive to magnets, very small particles are often electri- cally 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 em-

ployed as a final protection against adulterated prod- uct, as follows:

• Metal detection systems—the use of metal detec- tion 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 purchased—systems vary significantly in sensitivity, speed of detec- tion, and overall reliability.

aperture size—the ability of the system to detect a metal particle is a function of the sys- tem 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 rate—the higher the flow rate, typically, the lower the detection sensitivity.

Material composition—some 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 systems—the use of a prod-

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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 ineffec- tive if not perfectly executed.

• Statistically-based product inspection—finally, the entire approach described above must be supplemented with some level of statistically- based 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.

eNGiNeeriNG CoNtrolS VerSuS ProCedural CoNtrolS two types of controls—engineering and procedur-

al—are typically used in a comprehensive approach

toeliminationofmetalcontaminationinpharmaceu-

tical products. engineering controls are those built intotheequipment,system,orprocessesnotdirectly dependent upon human interaction for success. ex- amples 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 prop- erly 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 depen- dent upon individuals properly performing tasks defined in standard operating procedures, batch re- cords, work instructions, or other controlled docu- ments. Some of the keys for successful procedural controls include a clear and understandable proce- dure, 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 color- coding, poke yoke practices, and applicable verifica- tion systems can minimize non-adherence.

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CoNCluSioNS

the control and prevention of metal contamination in

pharmaceuticalproductsisachallengefromallperspec- Fda

tives—regulatory, 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 multi- faceted, comprehensive approach to ensure a sustain- able performance for prevention of metal contamina- tion.thisapproachmustincludeintentionalprevention 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 un- derstandthatbothengineeringandproceduralcontrols must be employed along with formal oversight (e.g.,

validation,qualification,training,verification,effective-

ness, and documentation). By enhancing our overall control strategy to include thiscomprehensiveapproach,weshouldexpectsuccess in the control of metal contamination of our products.

artiCle aCroNyM liStiNG

aPi

PM

uSP

active Pharmaceutical ingredient uS Food and drug administration Preventive Maintenance united States Pharmacopeia

aBout tHe autHorS

lorraine Mercurio is a project manager in the Product develop- ment 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.

reFereNCeS

1.

Fda, 21CFr211.67, (a) “equipment, cleaning, and mainte-

nance,” 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 Pharma- ceutical 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/Warninglet-

ters/2002/ucm144810.htm accessed 12/329/11. GXP

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