LABORATORY COMPLIANCE

Transcription

1 1 LABORATORY COMPLIANCE Jeanne Moldenhauer Vectech Pharmaceutical Consultants, Inc. Farmington Hills, MI INTRODUCTION Implementation of the Systems-Based Inspection Guideline for drug manufacturers in 2002 (FDA, 2002) has re-defined the expectations for the laboratory. Although the requirements for validation have been clearly defined for manufacturing equipment and have been required for many years, these expectations did not always get transferred to expectations for the supporting laboratory functions. This guidance document clearly states the regulatory expectations for the laboratory and the consequences of non-compliance. The document, although labeled guidance, reflects the thinking of the Food and Drug Administration (FDA) when interpreting the law as specified in 21 CFR. This chapter describes the regulatory expectations for the laboratory. OVERVIEW OF SYSTEMS-BASED INSPECTIONS The FDA has defined responsibilities that include providing comprehensive regulatory coverage for all aspects of the production and distribution of drugs and drug products. The purpose of this coverage is to ensure that these products meet the requirements of the Food, Drug and Cosmetic Act, 501 (a)(2)(b). Included in these requirements are both the facility inspection program and the surveillance and collection of samples for further analysis. 5

2 6 Laboratory Validation The Systems-Based Inspection Guideline document (FDA, 2002) was developed in order to provide a method for the effective usage of FDA resources when conducting investigations to evaluate whether companies are operating within current Good Manufacturing Practices (cgmp) compliance, performing pre-approval inspections, providing information to manufacturers regarding their state of compliance and how to best use the FDA s experience in the drug manufacture and distribution process. It is important to note that systems-based inspections have been established for device manufacturers for many years. Within this document, the FDA has identified six different systems within a drug manufacturing facility that represent the entire operation: The Quality System The Production System The Packaging and Labeling System The Materials System The Facilities and Equipment System The Laboratory System The FDA selects which systems are to be inspected during each facility visit. It is defined that the quality system must be reviewed during every inspection. The number of other systems reviewed is based upon the compliance status of the facility. At minimum, two systems must be reviewed in each inspection. Should any one system be deemed to be operating out of control, the facility is deemed to be noncompliant. A firm is considered to be operating in a state of control when it has established conditions, controls and practices to ensure that it complies with 501(a)(2)(B) of the Food, Drug and Cosmetic Act and the applicable sections of the GMPs. The GMPs are specified for drugs in 21 CFR Parts 210 and 211. With this type of classification, there are some items whose function may overlap into more than one system. The laboratory system may have components in many of the systems. For this reason, a brief overview of all the systems is described in the following section. THE SYSTEMS DEFINED The Quality System includes the overall compliance of the firm to the GMPs, internal policies, procedures and specification. Another area of review is the Quality Control Unit (QCU) and its defined responsibilities. For the purposes of the regulations, there is no distinction between quality assurance and quality control. Requirements for this system are based upon 21 CFR Subparts B, E, F, G, I, and K.

3 Laboratory Compliance 7 The Production System includes all of the manufacturing activities and procedures, excluding packaging and labeling. Also included in this system is the process validation of the equipment and software used. The requirements are based upon 21 CFR Subparts B, F, and J. The Packaging and Labeling System includes all of the activities and procedures necessary to control the packaging and labeling of drug products, including: label review, use, storage, issuance, destruction, and all of the operations to achieve these tasks. The requirements are based upon 21 CFR Subparts B, G, and J. The Materials System includes the various measures and activities that are used to control finished products or its components. It also includes the validation of computerized inventory control systems, distribution records and controls. The requirements are based upon 21 CFR Subparts B, E, H, and J. The Facilities and Equipment System includes those items that provide an appropriate physical environment and the associated resources for drug manufacture. Specifically, this encompasses the physical buildings, the equipment and its installation and operational qualification, calibration, maintenance, cleaning, and utilities. Requirements for this system are based upon 21 CFR Subparts B, C, D, and J. The Laboratory System addresses all of the laboratory procedures, method validations, laboratory equipment, laboratory computerized systems, laboratory activities, and the execution of the stability program. The requirements are based upon 21 CFR Subparts B, I, J, and K. DESCRIPTION OF THE REVIEW ITEMS FOR THE LABORATORY SYSTEM Adherence to Written Procedures One of the fundamental components of the laboratory control system is to ensure that all affected personnel follow the designated written procedures and appropriately document these actions. This review encompasses all phases of testing in the laboratory, from starting materials through to finished product. In prior times, inspectors evaluated the ability to follow procedures by reviewing the final approved documentation in the batch record. At this time, several reviews of the data had likely taken place. Within this inspection guideline, though, the inspector also takes the opportunity to observe the personnel using the procedures to evaluate their ability to follow the procedures as written. Many companies allow personnel to deviate from procedures on a routine basis, e.g., allowing the operator to do more than what is required in the procedure. This practice will be questioned with the observational type of review. The question of the inspector may be:

4 8 Laboratory Validation if this is perceived as necessary, why isn t it included in the procedure? If it is not necessary, why is it allowed? Supervisory personnel should consider the best demonstrated practices used in the laboratory and revise the procedures as necessary, such that all personnel do the same tasks in the same ways. Training and Qualification of Personnel Training and qualification of personnel can be evaluated in a variety of ways, e.g., observing their ability to correctly execute the procedure, evaluating how effectively they are able to complete the documentation, how frequently they are found using wrong methods or procedures and so on. For supervisory and management personnel this can also include the inability to find errors in paperwork reviewed. Another indication of poor training is excessive numbers of investigations due to operator error in the laboratory. Adequacy of Staffing for the Assigned Tasks Adequacy of staffing for the assigned laboratory operations is an area of evaluation. One of the indicators for this evaluation is whether all activities are being completed in a timely fashion. For example, one might consider the staffing to be inadequate if stability samples are routinely tested late. With inspectors spending more time in the laboratory and questioning laboratory personnel, one might be concerned as to whether by asking both laboratory personnel and laboratory management whether staffing is adequate will elicit the same answer. Adequacy of the Equipment and Facility for the Intended Use Evaluation of the laboratory includes an assessment regarding the adequacy of the equipment and the facility for the intended usage. Excessively cluttered or disorganized testing facilities tend to bring into question the adequacy of the facility. The inspector might also observe to determine whether each tester in the laboratory has sufficient space to complete their assigned tasks, without the risk of cross contamination or mix-ups. The equipment used in the laboratory should be appropriately validated/qualified, calibrated, cleaned, maintained and used. It should also be in good working order. Calibration and Maintenance Programs Established for Analytical Instruments and Equipment The laboratory should have an approved calibration and maintenance program. This may be part of the facility calibration program, if desired. It should cover all of the analytical equipment and instrumentation. Some of the sophisticated laboratory equipment requires specialized procedures to accomplish these tasks. It may be necessary to have these tasks performed via a service contract from the vendor of the equipment or their designated associates. When this is the case, it is important to have

5 Laboratory Compliance 9 a system that ensures that these tasks are accomplished within the specified intervals, that appropriately qualified individuals perform the testing, and that written procedures are followed. Validation and Security of Computerized or Automated Data Handling Systems All automated data handling systems, e.g., laboratory information management systems (LIMS), environmental monitoring systems, high performance liquid chromatography (HPLC) networks, must be validated and have appropriate security procedures. When evaluating the validation status of these systems, one must also take into consideration the components integrated to these systems, e.g., other laboratory equipment software, the facility network, systems, etc., which should also be validated. All applicable sections of 21 CFR 11 are followed. Reference Standards The procedures for reference standards should require that they be identified with the source of the reference standard, the purity and the assay value. When internal standards are prepared, appropriate tests should be established to show equivalency of the secondary standard to the current official reference standard. It is also important to ensure that the standards are stored appropriately and are not used after the expiration dating provided. System Suitability Checks on Chromatographic Systems, e.g., Gas Chromatography (GC) or HPLC Procedures should be established to ensure that system suitability tests are performed. Some of the newer microbiology systems, e.g., identification systems, use GC and accordingly require system suitability testing. Results from this testing should be reviewed and verified to be acceptable prior to proceeding with other testing. Specifications, Standards and Representative Sampling Plans Appropriate written procedure and standards should be written for all of the testing performed and the associated products and componentry. Sampling plans should be established and documented. Part of the documentation for sampling plans should be the rationale, i.e., the technical justification for the sampling plan. Adherence to Written Methods of Analysis Once the methods have been designed and written, they should be followed. This evaluation may also be determined by observation of the personnel performing the testing. Evaluation may also take place by determining how many deviations or investigations are documented for failure to correctly follow the procedure.

6 10 Laboratory Validation Validation/Verification of Analytical Methods For the purposes of this guidance document, analytical methods refer to both the chemical and the microbiological testing performed. Compendial tests technically do not require validation, but must be verified for the actual conditions used in the laboratory. Non-compendial methods must be validated. This includes tests like, bioburden recovery methods, neutralization procedures, D and z-value methods, new equipment test methods not covered in the compendia, etc. Validation requirements should be documented in a protocol or a standard procedure. Control System for Implementing Changes in Laboratory Operations Change control is a major focus of FDA in this inspection guidance document. The changes to be considered include methods, procedures, hardware and software. Expectations include reference documentation for all changes conducted in the laboratory for defined time periods, e.g., having a list of all changes for the past year. It is important that the change control procedure includes an evaluation of how the change affects the validation/qualification status of the item being changed. One should be able to technically justify the decisions made regarding whether system validation must be repeated. Required Testing is Performed on the Correct Samples It is important to have an established system that verifies that the correct testing is performed on the correct samples. The system established should be able to track and identify samples throughout the laboratory testing process. Additional precautions should be taken when samples are shipped outside the facility for testing. Another consideration in this area is that the required testing is performed within the allowable time allowances for initiating testing. For example, starting a test two weeks after collecting the sample, may not be appropriate unless data is available to show that the sample does not change its quality over the delayed testing time period. Documented Investigation into any Unexpected Discrepancy There will always be times when something unexpected or aberrant occurs. In this event, an investigation must be conducted. All investigations should be documented. When conducting these investigations, one should make sure that the review is thorough and that the problem is solved. There should also be consistency in the investigation procedures. For example, if there are six investigations for the same type of problem, the investigation conducted should have a similar level of detail. It is useful to have standard checklists or procedures of how to conduct investigations for specific types of problems. Complete Analytical Records from All Tests and Summaries of Results When testing records are reviewed, the expectation is that the record will be complete and accurate. There should be records available for each and every required test. If data summaries are generated, e.g., in the batch record or on a Certificate of Analysis (C of A), there should be complete test records to support the summarized data. Attention

7 Laboratory Compliance 11 should be paid to ensure that when multi-page records are used, that all pages be included in the documentation file. Quality and Retention of Raw Data (e.g., Chromatographs and Spectra) Raw data must comply with all rules for recording of original data. Equipment that requires different or subsequent integrations of data presents issues for laboratory managers. When the data needs integration, copies of the original raw data should be maintained. The ability to produce raw data can become complicated when multiple integrations are generated and the accepted data is automatically filed by the LIMS. Additionally, all data presented in reports and submissions should have the corresponding raw data stored in a way that maintains the integrity of the data for the required records retention period. Correlation of Result Summaries to Raw Data, Presence of Unused Data Each time data summaries are presented, e.g., batch records, management summary reports, or submissions, it is imperative that the data presented have supporting raw data for each summary result. Inspectors are also interested in whether all data was reported in the summary. In the event that other data is available, but was not included in the report, it will be subjected to scrutiny. Part of this scrutiny typically comes from a concern over whether the data was excluded to make failing results pass a test. Accordingly, one should have documentation that is based upon good science that justifies why the data is not included in the report. An example of this might be: this data was not included in the summary because the test was executed incorrectly on the XYZ equipment. The operator selected the Cycle 6 instead of Cycle 3 for the test. The sample collected was sufficient to re-test the exact same sample using the correct parameters. Adherence to an Adequate Out-of-Specification (OOS) Procedure, Including Timely Completion of the Investigation It is expected that an out-of-specification procedure be established for the laboratory. Many of the requirements for chemistry-related investigations arose from the interpretations of the law provided in a lawsuit between the US and Barr Laboratories. The FDA has issued a draft guidance document on handling OOS results, but the focus is predominantly chemistry. Unfortunately, translating these expectations to microbiology procedures may be difficult. The length of time required to complete investigations and determine whether the product is acceptable is important. Unfortunately, there is no direct guidance that explains what timely means. Many choose to believe that investigations should be completed in no more than 30 days.

8 12 Laboratory Validation Adequate Reserve Samples and Documentation of Reserve Sample Examination There are established requirements in the GMPs that describe the required reserve samples. It is also important that these samples be tracked, logged and examined. Inspectors are to verify that a sufficient number of samples for each product are retained and that required examinations have been performed and documented. Stability Testing Program and Documentation of Stability Indicating Capability of the Test Methods The stability program falls within the jurisdiction of the laboratory control system. It is expected that all required tests be performed and that they be performed at the specified time intervals. A pattern of failure to perform tests at the specified time intervals suggests that there may be insufficient staff in the laboratory to support the required testing. All tests performed should use validated or qualified methods and should agree with the specified requirements in the appropriate regulatory submission. The methods used must also be stability indicating, i.e., they are effective when testing samples over the shelf life of the product. Automated systems used to track and monitor stability testing and the associated results must be validated. Requirements for electronic records and signatures, as appropriate, must also be met. The actual raw data generated for stability testing should be reflected in the summary reports generated. Additionally, data reported in regulatory documents should have corresponding raw data on file. ACTIONS THAT TRIGGER REGULATORY ACTION There are several actions identified within the FDA Guidance Document that trigger a regulatory action, e.g., Warning Letters. They include: A pattern of failure to establish and or follow a control system for implementing changes in the laboratory operations One inherent problem is that the concept of pattern of failure is open to interpretation. How many occurrences reflect a pattern? Two? Three? As a history of inspections develops, one may be able to better define this parameter. The expected change control system should reflect those changes made to hardware, software, methods, and procedures. Pattern of failure to document investigation of discrepancies All discrepancies from established procedures should be thoroughly investigated. The investigated practices should be documented and tracked to ensure that they are completed and resolved.

9 Laboratory Compliance 13 Lack of validation of computerized systems and/or automated data collection systems Automated laboratory equipment and data management collection and evaluation systems must be validated. They must also comply with 21 CFR 11 as appropriate. Some companies are re-thinking the use of automated tracking systems, e.g., calibration or qualification status, due to the perceived headache of validating the software used. Other companies struggle with upper management to obtain the necessary resources to complete these validation studies. Another issue with laboratory systems is the fact that most validation departments have been geared toward engineering applications. The complexity of most laboratory equipment makes it difficult, if not impossible, for many validation departments to validate the equipment. Accordingly, they turn over the responsibility for validation to the laboratory. Laboratory personnel frequently do not have the hardware and software validation background to easily assume these responsibilities. Many companies may have to invest in training laboratory personnel in validation practices in order to comply with these requirements. Pattern of Inadequate Sampling Practices Systems should be established to ensure that all of the required samples are taken, that sampling procedures can be technically justified, and that sampling procedures are followed. It is also important that the methods used for sampling do not adversely affect the integrity of the sample. Lack of Validated Analytical Methodologies All analytical methods used, both microbiological and chemical, should be qualified or validated. Compendial methods are typically qualified and non-compendial methods are validated. It is important that laboratory personnel be able to locate easily the validation or qualification documentation for all methods used. Pattern of Failure to Follow Approved Analytical Procedures Procedures should be established that adequately and completely reflect the methods to be used. Operators should be sufficiently trained to follow the procedures at all times. Different operators should perform the same tests in the same way when following the procedures. Within the FDA guidance document, observational techniques will be used to ensure that procedures are followed rather than just reviewing completed documentation. As such, operators performing testing may not have the benefit of supervisory review of their documentation prior to being observed by FDA. Pattern of Failure to Follow an Adequate OOS Procedure Reviewers are looking for personnel to follow the procedure and to interpret and resolve out-of-specification (OOS) occurrences in a consistent manner.

10 14 Laboratory Validation Pattern of Failure to Retain Raw Data Companies must have the raw data to support all reports, summaries and submissions made. Although many companies have accidentally lost or damaged a specific record, this is not an acceptable practice. It is difficult to determine how much data must be missing or whether this will be interpreted based upon the criticality of the missing data that triggers a regulatory action. Lack of Stability Indicating Methods All methods used must be stability indicating. Pattern of Failure to Follow the Stability Programs The stability program submitted in the regulatory application should be followed as written. Lack of personnel to perform testing, or vacations times, or any other reason, does not justify failure to complete testing. In addition to be cited for stability testing not being performed, one will likely also be cited for not meeting the requirements for adequate staffing. CONCLUSION The laboratory control system is one of the most critical in a pharmaceutical manufacturing environment. In addition to being a defined system by FDA, many tasks performed in the laboratory are also part of the other established systems. The most recent guidance documents issued define requirements for the laboratory such that they carry the same weight as those expectations for production systems. Laboratory management has an ever-increasing responsibility to ensure that all tasks performed are compliant with established regulatory expectations. The most difficult task for many is obtaining the necessary resources to accomplish these tasks, until a negative regulatory action has been taken. BIBLIOGRAPHY Code of Federal Regulations, Title 21, Part 11 Electronic Records and Signatures, United States Government Printing Office, Washington D.C Code of Federal Regulations, Title 21, Parts 210 and 211, as revised April 1, 2000, including the general comments (preamble), United States Government Printing Office, Washington D.C

11 Laboratory Compliance 15 Compliance Policy Guides Manual, Chapter 4, Human Drugs, United States Government Printing Office, Washington D.C. Compressed Medical Gases Guideline, United States Government Printing Office, Washington D.C. Drug Manufacturing Inspections, CPGM , FDA, United States Government Printing Office, Washington D.C., Initial issuance as pilot program 1/1/2001 and finally issued 2/1/2002. Federal Food, Drug and Cosmetic Act, as amended. United States Government Printing Office. Guide to the Inspection of Computerized Systems in Drug Process, FDA, United States Government Printing Office. Guideline on the General Principles of Process Validation, FDA, United States Government Printing Office, Guideline on Sterile Drug Products Produced by Aseptic Processing. FDA, United States Government Printing Office, 1987.

12