Warning Letter Citations

Failure of pharmaceutical companies to adequately protect production lines from contamination and cross-contamination is a frequently cited Form 483 observation noted during establishment inspections. The focus on product contamination has increased significantly since the New England Compounding Center Recall, driven by product contamination resulting in multiple deaths from fungal meningitis.

Causes of Contamination and Cross-Contamination

Unfortunately, no single cause or event results in the contamination or cross-contamination of pharmaceuticals; otherwise, industry professionals would not need to traverse FDA’s enforcement page and read about the ongoing issues impacting the pharmaceutical industry. The causes are as diverse as the industry itself, with many high-profile incidents linked directly to poor good manufacturing practices (GMP) for finished pharmaceuticals. FDA placed much considertion, including the querying of industry, before scripting 21 CFR 211. The prevention of contamination and cross-contamination rests squarely on the shoulders of manufacturers and the practices they employ, or fail to employ.

One of the primary causes of contamination and cross-contamination is linked to a lack of properly documented and validated cleaning processes used by pharmaceutical manufacturers. Additionally, the improper labeling of drug ingredients and the lack of effective line clearance processes rate high on the list of causes for contamination and cross-contamination of products.

Tools for Preventing Contamination and Cross-Contamination

Equipment Cleaning

First and foremost, pharmaceutical manufacturers must establish written procedures that delineate the cleaning requirements for every piece of manufacturing equipment. The procedures must contain sufficient granularity to ensure that each piece of equipment can be adequately cleaned. In some cases, it may be necessary to remove equipment from the manufacturing environment to do a proper cleaning. Regardless, the cleaning process must be properly validated as validation is a salient requirement of 21 CFR 211 and a regulatory requirement for most regulatory bodies outside the United States.

When scripting the procedures for cleaning, multiple parameters require consideration for inclusion into each written procedure. For example, five components of the cleaning process that require consideration are:

• Equipment-related parameters

• Type of residual material (residues) that require cleaning and removal

• Identification of the types of cleaning agents to be used

• Specific type(s) of cleaning processes to be used

• Process variables associated with the actual cleaning of the equipment

Equipment-Related Parameters

From an equipment standpoint, each piece of equipment should have its own equipment file that captures all preventive maintenance activities, including cleaning and, if necessary, calibration. Included in the equipment file should be the installation qualification (IQ) for each piece of equipment. Equipment-related parameters that need to be considered include identification of equipment sections that may be a problem for cleaning, identification of the physical/mechanical properties of the equipment (for example, 17-4 stainless steel), and disassembly instructions as appropriate (that is, identification as to whether the equipment can be cleaned in place or requires removal from the production environment).

Residue Removal

Removal of unwanted residue is the underlying reason for the proper cleaning of equipment. Four elements that need to be considered in support of the removal of residue are proper identification of all residues requiring removal as part of the cleaning process, residue reactivity and toxicity, establishment of cleaning limits, and residue solubility.

Cleaning Agents

The selection of cleaning agents and the establishment of parameters for safe and effective use is immensely important. Some of the requirements to be considered when selecting cleaning agents include the chemical composition of the cleaning agent, instructions for properly mixing and using the cleaning agent, establishment of proper handling of cleaning agents, identification of special environmental considerations, and health and safety considerations. A material safety data sheet (MSDS) should be available for all cleaning agents selected and employed.

Cleaning Processes

The cleaning process and all parameters relating to the cleaning process must be clearly defined within a written procedure. Elements requiring consideration for inclusion in the procedure include:

• Defining whether the cleaning process is manual or portions of it can be automated

• Identifying whether the equipment can be adequately cleaned in place

• Availability of a user manual to assist with the cleaning process

• Training requirements for personnel performing the cleaning

• Time required to properly clean a piece of equipment

• Frequency of the cleaning process (daily, weekly, and so on)

• Testing or other requirements necessary before placing cleaned equipment back into service

Process Variables

All cleaning processes, regardless of the equipment being cleaned, have variables associated with the process. Process variables requiring consideration for equipment cleaning are the temperature required for the cleaning agent, the duration of each cleaning cycle, including the number of cleaning cycles required, the time frame allocated for each cleaning, operator variability, and the outsourcing of cleaning and maintenance to a third party versus performing the work in-house with the pharmaceutical establishment’s personnel.

Proper Identification and Labeling

Upon receipt, all drug ingredients must be properly identified and labeled. It is imperative that product traceability for drug ingredients be maintained to the individual lot/batch level. Additionally, it is incumbent upon pharmaceutical companies to properly store drug ingredients until such time as the ingredients are used. Special consideration should be made for special environmental requirements needed for product storage, as appropriate, for example, storage temperature.

Line Clearance

Pharmaceutical establishments are expected to have appropriate line clearance procedures in place to prevent potential contamination and cross-contamination. The line clearance procedure should clearly define lot/batch controls, documentation practices, product separation, product quarantine (if required), and the overall handling of materials during the manufacturing process.

Summary

FDA is extremely vigilant when it comes to ensuring that pharmaceutical establishments have adequate infrastructure in place, including written procedures, to prevent contamination and cross-contamination. Some of the most effective tools manufacturers can use are validated cleaning procedures that define, in great detail, the cleaning requirements for all pieces of equipment. Additionally, the proper identification and labeling of all drug ingredients and an effective line clearance process are needed as the first line of defense in the prevention of contamination and cross-contamination of pharmaceuticals.

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