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This discussion aims to outline an approach to metal contamination prevention that should achieve a level of control acceptable to all stakeholders.
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 prevention measures as a key means for avoiding contamination, application of in-process controls to remove the presence of metal particles, and 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 (CFR) 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 CFR 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 API manufacturing, International Conference on Harmonization (ICH) Q7 V. A. (5.1) states: "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 FDA's 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 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, and 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, 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:
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 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 40–50 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 three-tiered approach: Prevention, removal, and detection. Examples of each activity can be seen in Table I.
Table I: Summary of metal contamination control activities with example applications.
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.
Intentional actions are used 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.
Issues with metal contamination can often be traced to inadequate preventive maintenance (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.
Metal-to-metal contact should be prevented. There are alternatives to metal parts and, whenever possible, these should be used in high-risk areas. 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 systems cannot be avoided.
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 potential for catastrophic equipment failure.
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 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. Two primary methods are employed to effectively remove metal particles from product during manufacturing.
The 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.
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 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.
The use of metal detection systems is broadly accepted as effective for many manufacturing systems. However, the effectiveness of these systems is dependent upon a variety of factors.
Systems vary sigificantly in sensitivity, speed of detection, and overall reliability. The 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.
A system's flow rate can affect particle detection—the higher the flow rate, typically, the lower the detection sensitivity. 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.
The use of a product 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.
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 procedural—are 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 color-coding, poke yoke practices, and applicable verification systems can minimize non-adherence.
The control and prevention of metal contamination in pharmaceutical products is a challenge from all perspectives—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 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 understand that both engineering and procedural controls must be employed along with formal oversight (e.g., validation, qualification, training, verification, effectiveness, and documentation).
By enhancing our overall control strategy to include this comprehensive approach, we should expect success in the control of metal contamination of our products.
Lorraine Mercurio is a project manager in the Product Supply organization of Mallinckrodt, the Pharmaceuticals business of Covidien in St. Louis, Missouri.
Eldon Henson* is Director, Operations Technical Services at Mallinckrodt and serves as President of the Missouri Valley Chapter of the Parenteral Drug Association (PDA). firstname.lastname@example.org
*To whom all correspondence should be addressed.
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.
5. USP, Chapters <1> <788>, <797>, United States Pharmacopeia/National Formulary.
6. FDA, Warning letter to Berlex Laboratories (March 11, 2002), www.fda.gov/ICECI/EnforcementActions/WarningLetters/2002/ucm144810.htm accessed 12/329/11.
This article was originally published in the Journal of GXP Compliance, 16(1), 51-56 (Winter 2012).
For related article, see also "Elemental Impurities" in the Nov. 2012 issue of Pharmaceutical Technology.