Unwanted and potentially dangerous chemical or biological contaminants in pharmaceutical manufacturing have long been an area of concern. These contaminants can lead to unpredictable pharmacological effects or super- or sub-potency of the active drug substance. Worse, they may be toxic.
Because of the potentially dangerous implications of contaminants on patient safety, the FDA, through its Current Good Manufacturing Practices (cGMP) regulations, requires manufacturers to employ a number of technical and scientific techniques in the manufacturing cycle. These techniques share a common goal: to provide a high level of assurance that finished drug products meet their intended and defined specifications. The FDA calls this goal validation.
To understand how these techniques provide this assurance, it is important to understand how the specifications for active drug substances and excipient compounds originate. Specifications for active drug substances and the inactive chemicals with which they are compounded (“excipients”) that are approved by the FDA to be sold in the United States are found in the United States Pharmacopeia (USP) and National Formulary (NF). The compendia not only identify the types of compounds, but also the analysis mgthods, and reagents, and acceptance levels that are required to be used to test and release products.
The USP/NF section on General Notices, Foreign Substances and Impurities, however, states:
...it is manifestly impossible to include in each monograph a test for every impurity, contaminate or adulterant that might be present, including microbial contamination. These may arise from a change in the source of material or from a change in the proceýsing, or may be introduced from extraneous sources. Tests suitable for detecting such occurrences, the presence of which is inconsistent with applicable manufacturing practice or good pharmaceutical practice, should be employed in addition to the tests provided in the individual monographs.
This is one of the key reasons the FDA is taking a new look at how it applies cGMPs in the pharmaceutical industry. In September 2002, the FDA announced this initiative as “Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach.” In part, this initiative will focus the validation efforts of manufacturers on materials and manufacturing systems that they have determined could lead to potential or actual patient risk due to contamination.
The Lifecycle Approach
The FDA has indicated that a Lifecycle Approach is a critical element of effective validations. When viewed in light of the USP/NF General Notice and the FDA initiative, contamination control and assurance in the pharmaceutical manufacturing process becoýes a sequence of activities that is part of the product Lifecycle. As such, the assurance methods and activities to control contamination are dynamic, and must constantly be refreshed when material or process changes occur, or when new information or technology becomes available.
First, the company must determine all the sources and types of biological and chemical contaminant introduction in the process and their impact on the final product through technically and scientifically sound risk-based methods. After determining the probability of occurrence, severity, or impact should it occur, and the existing levels of detection for each source, a risk of occurrence can be derived. When these risks are reviewed against accepted patient or human safety standards, key contaminant sources and the methods of assuring their control can be identified for subsequent validation.
Many technically sound risk-based techniques such as Failure Mode Effects and Analysis (FMEA) can be used for these evaluations. However, a technique that originated with the FDA in food safety, Hazard Assessment and Critical Control Points (HACCP), is growing in popularity for pharmaceuticals and medical devices. This technique provides companies with the ability to succinctly identify the critical sources and types of contamination as well as the mechanisms for controlling them in material and manufacturing processes.
Once the potential contamination sources are identified, the second activity in the Lifecycle approach is to conduct scientifically and technically sound qualification studies that provide evidence that contaminants can be controlled to the defined levels desired. These qualifications are required to not only demonstrate control under nominal process conditions, but also under conditions where the material or process is under stress. For FDA purposes, these prospective studies are defined as Protocols, and take the form of Installation Qualifications, Operational Qualifications, and Performance Qualifications. At a minimum, pharmaceutical contaminant process validations should consider the qualification of any:
* Active and excipient materials and their suppliers
* Microbiological bioburden of materials, processes, and environment
* Cleaning, disinfecting, and residue control of process equipment
* Air handling and purification
* Employee health, hygiene, and sanitation
* Production of water used in the process or for cleaning
* Manufacturing process and activity degradation
* Lubricants or process aids used in manufacturing
* Pesticides used in the manufacturing processing areas
* Computers and software that control any manufacturing or associated processes
The Impact of Change
Bnce these studies have been concluded, the materials, processes, and quality systems that support them have demonstrated themselves as valid. However, since change is inevitable, this validation must be reviewed for ongoing applicability when changes are made to any key factors contained in the original study. This becomes the Lifecycle aspect of validation. Changes that can impact the original state-of-validation can occur in many ways; any change in components or materials, suppliers, a supplier’s process, or in a supplier’s supplier may impact current contamination controls. Seemingly innocuous changes in cleaning and disinfection may become a source of change in the ability to provide assurance contaminants are being controlled. Because ‹any processes today are computer controlled, changes to process control software may have significant impact on contaminant assurance.
All changes that could impact the original risk assessment assumptions must be reviewed for impact to the current validation. In some cases, this may involve revisiting the original risk assessment to determine if the risk factors need to be recalculated due to the change. If it is determined that the change could impact the current validated assurance levels, the change must be studied through a re-validation activity prior to implementation. But the validation dynamic is not only limited to changes made by the pharmaceutical firm or its suppliers. Companies are also expected to be aware, and act on, information from outside sources that may have a bearing on their original risk assessment. Items such as revisions to safe levels of contaminants, new toxic compounds, and mutated strains of microbiological contaminants can be reported in the literature and press. Companies may also become aware of a contaminant issue that occurred either internally or at a competitor for a process or material similar to the item in question. Likewise, information gathered from adverse reports of the drug use in patients may lead to information that requires the company to challenge its original risk assessment assumption and testing.
The above review process is useful on an individual change basis: a “micro” scale, if you will. Even if no intentional changes were made or have occurred, and all processes have operated normally and within limits, pharmaceutical companies are still required to annually review an amalgamation of all information and data sources of nonconformance to the quality system. This is done in an effort to determine if there are any negative trends and shifts in assurance levels that may be occurring on a “macro” scale and be observable only when a year’s worth of information is compiled. This is a requirement of the drug cGMPs under 21 CFR 211.180(e).
Contamination in finished pharmaceutical products is an area that is focused on by the FDA since it can lead to major regulatory or patient safety issues for companies unless they are controlled through proven, effective mitigation techniques and control. Because each and every tablet or capsule produced cannot be analyzed, companies must have technically and scientifically sound methods in place to demonstrate assurance that the type and levels of contaminants that could be in each of those products are under control.