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Reserve samples of test and control articles must be retained for at least one stability time point after the completion of the study.
Audits and regulatory warning letters are increasing in the pharmaceutical industry. The biggest area of noncompliance in pharmaceutical development and production is laboratory quality control1 (Figure 1). Yet, laboratory quality control is one of the most critical components of drug development.
The cGMP regulations are designed to ensure that products meet safety, efficacy, purity, and stability standards. Compliance with cGMP regulations is verified by reviewing a company's documented adherence. Because random regulatory inspections of commercial laboratories can be conducted anytime—without prior notification—experts suggest that all commercial laboratories conduct routine comprehensive cGMP self-evaluations.
This article identifies key components of a laboratory control system and discusses current cGMP practices and challenges.
Facility personnel designate cGMP areas on the building's floor plans. To carry out all cGMP operations consistently, facilities must be of adequate size and design; the general condition of the airflow, temperature, and humidity systems must be monitored to ensure that all laboratory operations are carried out in a controlled environment. Work areas must be kept clean and uncluttered, cleanliness maintained and assessed continuously. Separation of test articles must be maintained to ensure that the samples are not exposed to contamination or stress, and prevented from mixing or handling errors.2
A lack of adequate space for new equipment is a common problem because laboratories are usually designed to hold existing equipment, which deteriorates slowly. When a new piece of equipment is needed, it must be properly qualified for its intended use. Then, regular maintenance and calibration must be performed to ensure that the results generated are valid.
Figure 1. Common cGMP deficiencies for 2004â2005.1
Maintenance and operation should be based on standard operating procedures (SOPs) or operating manuals. Equipment logs, a vital source of information to demonstrate overall compliance, are maintained to document adherence to SOPs, calibrations, and to report adverse events. All equipment must be categorized by cGMP status and by cGMP critical or noncritical use. Equipment with critical status requires preventive maintenance and calibration and must undergo full qualification and validation. Other categories of equipment may require qualification or validation, based on the specific equipment use. Automatic, mechanical, and electronic equipment all require validation.
All laboratory processes, including facilities, equipment, analytical methods, and computer programs used in the analytical testing of pharmaceutical products must be validated.2 Following an initial evaluation, every supplier is audited and qualified. Validation includes several different qualification activities: a validation master plan outlines the overall approach to be taken for validation. User requirement specifications (URS) and functional requirement specifications (FRS) are defined for design qualification (DQ) or for subsequent validation testing. URS specifies the users' needs, as well as any regulatory requirements. FRS are statements that specify what the system must be able to do to meet the users' needs. These act as key reference points of validation.
Qualification ensures that a specific process has met its pre-determined acceptance criteria. Qualification involves installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ). IQ verifies and documents that the installation and any modification of the facility or equipment comply with the manufacturer's approved design and recommendations; OQ verifies and documents correct operation of the system under working conditions during which individual tests with defined acceptance criteria are performed; and PQ verifies and documents that the facility or equipment performs specific testing for its routine use within the assigned acceptance criteria.
PQ is a method-related operation that the analyst performs. Many instruments can be on hold pending the formal qualification. Outsourcing can be an alternative to speeding the qualification process.
Validation is documented testing, performed under highly controlled conditions, and demonstrates a process that consistently produces a result that meets predetermined acceptance criteria. In a validated process, it is possible to retest the system and obtain conformance to specification. Revalidation is performed at periodic intervals or when a validated system is changed (e.g., relocation or a software upgrade). All computer-associated systems should have defined storage capacity and regular and emergency back-up procedures that are defined during validation. The system should be challenged for accurate data transfer, data retrieval, and integrity.
Calibration is performed for process and system monitoring and control. Instruments differ in their calibration frequency based on their use. The written procedures should include the elements of calibration intervals, accuracy limits, and remedial actions if the system does not meet established requirements. Periodic preventive maintenance is vital to ensure that all processes operate in their validated state.2
Documentation reflects how a product is produced, tested, packaged, and stored. Procedures are designed for controlled assessment and implementation of planned changes. Each document should be uniquely identified and readily available. Documentation SOPs are developed using regulatory requirements as a minimum standard, and reviewed to ensure that regulations are met or exceeded. Procedures should be written clearly for all operations and reflect actual practice. Procedures should also adequately govern the quality and integrity of the data. SOPs have to be properly authorized and dated, and periodically reviewed for current applicability and changing regulatory requirements All operations are to be carried out in compliance to the current SOP version.
Laboratory documentation and records must be current, permanent, legible, accurate, clear, consistent, and complete. Any work not documented is considered not performed. Laboratory records should focus on both the 'what' and 'how' of data capture. Formal checks should be in place to challenge the accuracy and integrity of the written record. The analyst and reviewer must review, sign, and countersign the written record. Electronic records should be created and stored. A carefully prepared record allows for re-creation of an event in case of an investigation.
The quality and acceptability of raw materials, reagents, and solutions must be described and verified at the time of receipt and use. The identity and concentration of reagents should be documented and labeled. Storage requirements and expiration are to be documented and followed. Primary and back-up suppliers for all materials or equipment being used in any cGMP operation must be qualified and approved.
Equivalent alternates should be provided for specific branded products used in methods or procedures. This prevents the need to requalify if a manufacturer is unable to provide a required reagent.
Accountability should be maintained for all test and control articles by documenting the transfer of samples from the point of collection to the test facility. Proper labels should be used to identify the product, batch number, tracking number, label claim, and storage condition.2
Procedures should ensure that the distribution, storage, and handling of all test articles prevent contamination and deterioration.4 Storage containers should be appropriately labeled and assigned. Reserve samples of test and control articles must be retained for at least one stability time point after the completion of the study. Test and control articles should be maintained under proper environmental conditions. At any point, the actual amounts of product in inventory and the accountability records should reconcile with one another to ensure the integrity of the sample custody. Analytical laboratory personnel must document receipt of all test articles. The test article should be properly stored and segregated, based on its status during incoming, testing in progress, and testing completed. Procedures should be in place, applicable, and followed for characterization and stability testing of article. The testing required will depend on the process and the intended uses of the product, and may be applied during in-process, bulk, release, or stability.
Table 1 provides an example of analytical testing of a biopharmaceutical product.3,4 Identity, strength, purity, and potency assays should be qualified or validated. Accuracy, precision, specificity, and reproducibility of test methods should be established during validation. Technical transfer of the analytical methods should be performed with a qualified laboratory. Test article characterization for each batch or stability condition has to be documented. The analytical raw data and the reported results should be verified for data accuracy and integrity. Any deficiencies or deviations must be reported.
Table 1. Laboratory Testing Required for a Biopharmaceutical Product
Current and approved analytical methods should be used for testing of samples. A copy of the draft method should be part of the ancillary documentation until the official method is published. System suitability results and acceptance criteria for the assay, per method, should be documented in the laboratory notebook.
Reference material should be fully characterized and documented, properly stored, secured, and utilized during testing.4 Identity tests for products are usually confirmed by comparison with the appropriate reference standard (Table 1). Reference standards should therefore be periodically evaluated for meeting appropriate specifications. Laboratory cultures and labile reagents have to be stored under suitable storage conditions.4
CGMPs require an adequate number of qualified personnel with practical experience to perform the assigned tasks.4 Training in cGMP practice is provided by a qualified trainer and periodically assessed. An active cGMP training program should be current and ensure that personnel are adequately trained and perform the functions they are responsible for, follow procedures for necessary precautions, and review laboratory data. Summaries of training and position description should be verified, maintained, and current. Ideally, the training department provides general training (e.g., weighing, pH), and specific laboratories provide functional training (e.g., HPLC, ELISA).
A deviation is an event in which procedures are not or cannot be followed. Investigations, which should attempt to identify the root cause, involve initial observations, immediate action, and corrections to ensure that the problem does not recur. Final disposition of any affected products should also take place. The formal report generated includes corrective actions taken on deficiencies previously exposed by audits. Subsequent inspections should guarantee that all corrections have been implemented in a timely manner.
Current GMP expectations include what the regulatory agencies consider feasible and viable. "Best of industry" practices extend beyond written regulations. The percentage of time a laboratory scientist must allocate for common GMP activities is estimated in Figure 2. Time is allocated equally for both testing as well as compliance activities. It is critical for everyone to stay abreast of current cGMP requirements and guidelines. Implementing the cGMP regulations and guidelines enables the industry to prevent, detect, analyze, and correct problems and failings, ensuring that drug products are consistently high quality.
Figure 2. The estimated percentage of time required for common cGMP activities in the laboratory
In the past, regulations were created as a reaction to problems and inspections were based on a checklist. Today's regulators encourage a proactive approach. Strategies include implementing and integrating quality systems substantiated on new technological advances and risk-based approaches. The FDA5 describes risk-based approach as one
"designed to establish product quality . . . founded on sound science and engineering principles for assessing and mitigating risks of poor product and process quality in the context of the intended use of pharmaceutical products."
FDA expects the industry to encourage and monitor compliance and to implement and measure sustainable compliance. The industry is also expected to cooperate with the regulatory agencies in providing the complete information requested within a reasonable time frame. Shared awareness and understanding of the cGMPs are key to the success of the pharmaceutical industry and its regulators in delivering quality products to the public.
ELIZABETH THOMAS is a senior research scientist at Wyeth Research, 401 N. Middletown Rd., Pearl River, NY 10965, tel. 845.602.4747, ThomasE@wyeth.comANITA GROCHULSKI, RIPAL PATEL, SAM M. GEORGE, and LING ZHANG are part of Chemical and Pharmaceutical Development at Wyeth Research.
1. Horan RC. FDA cGMP Inspection. FDA cGMP China Training Program. 2005; Beijing, China.
2. Vesper LJ. GMP in Practice: Regulatory expectations for the Pharmaceutical Industry. Serentec Press, Raleigh, NC 2000.
3. Avallone HL, Beatrice MG, Sze, TT. Food and Drug Administration Inspection and Licensing of Manufacturing Facilities. Bioprocess Technol. 1991;13: 315–40.
4. FDA Biotechnology Inspection Guide. www.fda.gov/ora/inspect_ref/igs/biotech.html
5 Pharmaceutical cGMPs for the 21st Century — A Risk-Based Approach: Second Progress Report and Implementation Plan. http://www.fda.gov/cdr/gmp/2ndProgressRept_Plan.htm