Regulatory Compliance of Equipment Qualification

The requirement of European and US companies for on-site auditing of active pharmaceutical ingredients (API) manufacturers has added pressure to countries like India and China to conform.

Yet compliance is not defined identically across the international playing field. Thus, it has become important and practical to harmonise GMP and create a global quality standard. The overall harmonisation of GMP regulations presents a long and challenging path. One critical step on that path is having an international standard for equipment maintenance and qualification compliance.

Regulating equipment

Although it will likely be a while before all countries who are players in the pharmaceutical industry have all GMP requirements completely in sync, the language of general equipment regulations is largely comparable across international regulations.

These standards are described in nearly identical language by the US FDA’s Code of Federal Regulations (CFR), the International Conference on Harmonisation’s (ICH) Q7- Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients and the India Ministry of Health and Family Welfare’s Schedule M.

There are also comparable regulations from ISO/IEC 17025 and the World Health Organisation’s (WHO) GMP guidance. The People’s Republic of China State Food and Drug Administration (SFDA) describes brief, general equipment requirements in their Drug Administration Law.

Apart from the SFDA, the above mentioned regulatory authorities’ GMP regulations expressly stipulate that equipment must be suitably designed and constructed for the manufacturing and testing of API and finished drug products. Equipment design, size and location must be appropriate for its operation, maintenance and cleaning.

Regulations specify that any parts of the equipment that come into contact with the drug substances or products must not cause adverse affects (beyond established specifications). Substances used for equipment operation (eg lubricants, coolants) must not come into contact with the drug components. Additionally, equipment must be qualified, cleaned, maintained and calibrated for its intended use.

Due to the lack of detail in describing specific obligations in regards to qualification and calibration, there have been variable interpretations to the GMP regulations. While international GMP regulations emphasize equipment compliance with both process and testing instruments, this article focuses specifically on regulatory compliance in the qualification of laboratory testing equipment.

Instrument qualification is considered the foundation for producing quality laboratory data. Thus, ensuring laboratory instrumentation is qualified to GMP standards is a crucial aspect of the quality system. Equipment compliance is a point of focus during inspections by regulatory authorities. Equipment nonconformance is frequently documented as an observation on FDA 483 warning letters.

Examples of such observations read: “No or inadequate maintenance and cleaning of equipment”, “Insufficient intervals for equipment calibration” and “Routine calibration of mechanical and electronic equipment is not performed according to a written program designed to assure proper performance.” For Asian API sourcing companies undergoing on-site auditing, these types of observations by inspectors could be devastating to business.

Analytical instruments used for testing are becoming increasingly complex and sophisticated. Pharmaceutical testing depends on precise and accurate data from these instruments. Thus, it is necessary to qualify equipment to ensure that it will perform as intended, generating reliable, reproducible results.

The qualification of analytical instrumentation for GMP compliance was the focus of a workshop by the American Association of Pharmaceutical Scientists (AAPS) in 2003. The attendees employed a scientific approach to develop a concrete guidance to the qualification process.

Their goals included establishing clear definitions of responsibility, an effective and efficient qualification process and ultimately publishing a paper for submittal to regulatory agencies.

The resulting white paper served as the basis for the United States Pharmacopoeia (USP) general monograph <1058> for Analytical Instrument Qualification (AIQ). The contents now serve as the international standard of GMP compliance for qualifying analytical instruments.

The analytical laboratory houses numerous kinds of equipment involved in testing with varying degrees of sophistication. There are, therefore, varying degrees of complexity for ensuring equipment is qualified for its intended use. USP divides laboratory equipment into three groups of respective complexity in monograph <1058>.

For the simplest laboratory equipment, only visual observation is needed to confirm it is qualified to be used. USP describes this simple equipment, such as stirrers and vortex mixers, as belonging to Group A Instruments.

USP describes increasingly complex equipment as Group B Instruments. Written procedures must be followed to assess these instruments’ suitability. Group B Instruments, such as pH meters, balances and pipette, are still relatively simple. Therefore, testing for their qualification is generally straightforward and specifications are readily identifiable.

Group C Instruments encompass instruments of the highest complexity, such as high performance liquid chromatographs (HPLC), gas chromatographs (GC) and atomic adsorption (AA) spectrophotometers.

This highly specified, sophisticated class of equipment must be subjected to extensive testing before it can be considered qualified for use. In <1058>, AIQ is described as the means of ensuring the instrumentation is suitable for its intended use. AIQ confirms that the instrument produces reliable and consistent data.

The big four

AIQ is composed of four phases of qualification events: design qualification (DQ), installation qualification (IQ), operational qualification (OQ) and performance qualification (PQ). These four qualification phases are also described by the WHO’s Good Manufacturing Practices Guide for Quality Assurance of Pharmaceuticals.

The SFDA’s Drug Administration Law describes IQ, OQ and PQ in their GMP requirements, but excludes the DQ phase. It is, however, mentioned in the SFDA’s technical book, Guidance for the Validation of Drug Production.

Each qualification event is a set of documented activities to establish the instrument’s qualification for use. Although the specifics of the tests are not currently described in the USP monograph, the Analytical and Life Sciences Systems Association (ALSSA) has shed some light on the subject. In 1996, they published a voluntary guideline to IQ, OQ and PQ procedures.

General requirements of the qualification as a whole are that there are documented procedures and that test methods are designed by qualified personnel. The frequency of qualification events and responsibilities for all aspects of the qualification must be clearly defined.

All performed activities of the qualification phases must be documented and stored. If any significant changes to the environment occur that could affect instrument performance, applicable qualification phases must be repeated. These are universal requirements described internationally by most regulatory authorities.

DQ is the first stage of qualification, generally performed prior to purchasing the equipment. The instrument developers and manufacturers are ultimately responsible for DQ when designing the instrument. Responsibilities include setting functional and operational specifications for the product. Additionally, manufacturers should notify consumers of any defects that may be found after the product is released and provide user training and support.

Users must ensure product design is suitable for the intended use and evaluate vendor qualification, though this is generally considered unnecessary when purchasing commercially available off-the-shelf systems from reliable manufacturers.

The IQ is performed upon initial instrument setup, usually at the time of instrument delivery or after transporting the equipment to a new location. The IQ phase confirms and documents that the instrument has been delivered as specified, that all key components are present and that it is properly installed in a suitable environment.

For example, the installation site must conform to the manufacturer’s recommendations (eg lighting, electricity, temperature) and have enough space for operating, maintaining and cleaning the instrument. A successful IQ must precede the OQ and PQ testing.

OQ demonstrates that the analytical instrument functions as specified. The degree of testing in this phase varies based on the instrument and its level of sophistication.

Fixed parameters, such as wavelength and voltage input, are examined to confirm that they conform to manufacturersupplied specifications. Fixed parameters do not change and do not need to be checked again (as long as the instrument is not moved), so alternatively, they could be performed in the IQ phase.

Next, tests are performed to ensure data is stored, backed up and archived according to written procedures. Lastly, tests are performed to evaluate instrument function and determine if it performs as intended (to manufacturer-supplied specifications).

The test procedures and specifications for OQ must be clearly defined for GMP compliance, yet users are often unclear on these specifics. Tests are specific to the instrument undergoing qualification. Standard selection is a significant consideration in OQ testing (if applicable to the instrument). If possible, it should be performed using reference standards traceable to certified standards.

Activities in this qualification phase may be performed on each individual component of the instrument (modular approach) or on the entire system (holistic approach). Specifications must be set to a reasonable level, and it is not usually practical for these limits to match the manufacturer’s instrument specifications. Their specifications are met under optimal instrumental conditions and can be more stringent than is required by the limits of many applications.

The manufacturer’s specifications can be taken into consideration when setting limits for OQ but must be considered together with the instrument’s intended applications. The required frequency of OQ testing should be set appropriately based on the type, usage, stability and specifications of that equipment. The frequency and tests performed within the PQ are also factors to consider when determining OQ frequency.

In general, the frequency of OQ testing should be set such that the OQ testing has a high probability of passing. In practice, preventative maintenance often precedes recurring OQ testing for practical purposes to enhance performance. If PQ testing includes all relevant performance assessments contained in the OQ, then repeated OQ testing may be omitted altogether.

PQ is a routine demonstration to show that the instrument continues to perform to specification for its intended purpose. PQ testing procedures should be developed based on good science and the instrument’s frequency of use in the analytical laboratory. These tests may resemble those performed in the OQ, perhaps with varying specifications.

As with the OQ, testing may be performed using a modular or holistic approach. The regularity of the PQ testing depends on the characteristics of the instrument and testing which it performs. PQ is often performed in practice, such as with a system suitability assessment, prior to sample analysis.

Performance criteria and specifications must be clearly defined for the PQ, as well as testing intervals and response to nonconforming results. Maintenance or repair must follow any PQ tests that fail to meet specification. In this case, testing is repeated until the results conform. Preventative maintenance is often recommended for certain equipment to avoid such instances.

Users’ responsibility

Users are ultimately responsible for qualifying the instrument, designing qualification protocols and data quality. It is the role of the quality unit to ensure the AIQ comply with GMP regulations, to ensure processes are being followed and that valid, documented data supports the intended use of the equipment.

The overall complexity of the regulations on a whole and lack of detail in equipment guidelines can lead to variable interpretations of requirements. With analytical instrumentation qualification, instrument-specific obligations are not defined and users must be diligent to succeed in complying with GMP requirements.

Technology continues to develop more intricate and advanced instruments. GMP equipment qualification requirements will undoubtedly continue to evolve and adapt to cover the greater complexities. Countries that strive to make a name in the pharmaceutical industry must come up to current standards if they hope to keep up with the progressions that lie ahead.