GMP NOTEBOOK

EFREM H. ZARET, PH.D.

Quality Control Laboratories

Control of testing laboratories is a never ending concern

Laboratory error is a significant cause of recalls and FDA Inspectional Observations (483s). Inspection of quality control laboratories therefore requires special consideration and care. The Guide To Inspections Of Pharmaceutical Quality Control Laboratories (www.fda.gov/ora/inspect_ref/igs/pharm.htm) begins as "In addition to the general approach utilized in a drug cGMP inspection, the inspection of a laboratory requires the use of observations of the laboratory in operation and of the raw laboratory data to evaluate compliance with cGMPs and to specifically carry out the commitments in an application or DMF. When conducting a comprehensive inspection of a laboratory, all aspects of the laboratory operations will be evaluated."

Recent warning letters provide insight into the Agency's expectations with respect to operation of quality control labs (visit www.labcompliance.com for details). This list of horrors is an eye opener given the current state of sophistication that exists in our industry.

List of Horrors

Recent warning letters provide insight into the Agency's expectations with respect to operation of quality control labs (visit www.labcompliance.com for details). This list of horrors is an eye opener given the current state of sophistication that exists in our industry.

• Insufficient detection of impurities, inadequate analytical methods validation, missing raw data, lack of scientifically sound test procedures, failure to identify unknown peaks during the testing for organic volatile impurities, lack of adequate training for laboratory analysts and manufacturing employees;

• Failure to perform the required USP testing on each production "batch" of the product Anhydrous Caffeine USP;

• The (HPLC test) method currently used to assay caffeine has not been shown to be equivalent to, or better than, the current USP method;

• The primary caffeine USP reference standard is not used, and the secondary reference standard in use has not been qualified;

• The reference standards used to perform the caffeine tests are not stored under adequate conditions;

• Laboratory notebooks do not document critical information including test methods, reagents used, weights of samples, and drying times and temperatures achieved during testing;

• The equipment used to analyze the caffeine product was not calibrated prior to use;

• The laboratory hood is not certified;

• Laboratory equipment maintenance logbooks are not maintained;

• The laboratory bench, sample jars and equipment are dirty and covered with a white powdery material;

• There is no established GMP training program for the firm's employees;

• No or insufficient method validation, expiration dates and storage conditions;

• No chromatographic system suitability testing;

• Missing laboratory records, missing chromatograms and spectra, missing stability test records;

• Standard weights, sample weights and calculations are not recorded;

• No written procedures for any micro-biological tests are performed;

• Balances have not been calibrated against ASTM conforming weights;

• No established calibration specifications for the infrared spectrophotometer exist when the spectrum of polystyrene is recorded;

• Raw data has not been reviewed and maintained;

• Test records are released before review and approval;

• Results of stability testing are not traceable to the batches produced at the manufacturing site, missing raw data, no testing of detector linearity, no testing of accuracy of temperature settings for column heater and detector, inadequate calibration procedure for GCs and GC headspace unit, calibration raw data and results obtained for performance qualification of analytical instruments not checked for accuracy and completeness by a second analyst or supervisor; and

• The calibration procedure for HPLC systems is inadequate in that it did not include integrator and detector's linearity, injector's reproducibility and accuracy of temperature settings for column heater and detector.

A Control System for Labs

The Compliance Program Guidance Manual dealing with drug manufacturing inspections (CPM 7356.002) discusses the control system for laboratories and lists a number of areas that should be covered. These include change control, standard operating procedures, personnel training, calibration and maintenance of laboratory equipment, validation of computers, control of reference standards, system suitability checks on chromatographic equipment, representative sampling plans, validation/verification of and adherence to written analytical methods, OOS investigations and documentation, adherence to the written OOS procedure, raw data retention and complete analytical records of all tests and summaries of results, and demonstration that analytical methods used in the stability testing program are stability indicating.

Some of these areas are part of general cGMP compliance for all aspects of drug product manufacturing, but others are specific to laboratories.

Control of raw data is critical, and a laboratory is no better than its data. Laboratory SOPs should ensure that data is traceable from its acquisition through its verification by a second person and preparation of the data summaries. The SOPs should also specify the data retention policies and prescribe the data retention procedures. Chromatographic data should refer to the sample analyzed, the system used and the electronic data file that is stored on the system. If a paper printout of the data has been produced, that should be cross-referenced to the notebook or datasheet that was used to describe sample preparation, analysis and the results. If an electronic file is maintained, the SOPs should discuss compliance with Part 11.

While on the subject of laboratory data, we must consider out-of-specification results. Every laboratory generates unexpected data, and the evaluation of that data must be done according to a well-defined, rigorous procedure that can separate laboratory error from defective product or materials. The SOP(s) dealing with investigation of unexpected and/or OOS results must provide sufficient information for the decision as to whether the data is truly OOS or just an error in the laboratory. OOS investigations must be timely and complete; they must be completely and thoroughly documented and properly reviewed. The investigation must consider the root cause of the OOS or lab error, and it must include consideration of corrective and preventative actions.

Equipment not Qualified/Calibrated

I am constantly amazed at laboratories utilizing equipment that has not been qualified and calibrated (21 CFR 211.160 (b) (4)). Although it is unusual to find balances that are out of calibration, I often find that the check weights that are used daily have not been certified or are not regularly certified.

Calibration of chromatographic systems often is incomplete because the individual modules have not been calibrated, or flow rates, pressures, temperature controls, etc., have not been calibrated individually. Thermometers are often not routinely calibrated against certified standards.

All of these observations should be prevented by compliance to SOPs that are specific to the laboratory. The SOPs should discuss the routine validation/qualification of lab equipment, and must include consideration of preventative maintenance. For chromatographic equipment, the SOPs should also describe the use of system suitability testing to verify a system's proper and reproducible operation. System suitability procedures are a required part of the analytical test method.

While on the subject of lab equipment, I must mention equipment log books. Records of the use and non-routine maintenance of laboratory equipment is basic and should be covered in the laboratory SOPs. The use of chromatography columns should also be recorded and be traceable for any given column.

Another common problem involves the storage and handling of analytical standards. Primary analytical standards must be stored and handled according to their specifications, and those procedures should be documented in SOPs. It is not uncommon to find USP standards stored in a controlled humidity chamber, which is, however, not monitored to ensure that the humidity and/or temperature are within specification. Quite often, the storage conditions are not recorded or logged.

If primary standards are used to prepare secondary analytical standards, the procedures and methods used to qualify the secondary standards must be fully documented and be covered by SOPs. The storage of secondary standards requires the same care as the primary ones.

Handling Test Samples

Procedures for storage and security of test samples submitted to the lab are another topic that should be covered by SOPs. Is the receipt logged with time and date? Where are the samples kept before, during and after analysis? Is there sufficient sample to provide an adequate reserve sample and how long will the reserve sample be kept after its analysis is completed? Do not forget that some samples require special storage conditions and protection from humidity, light and oxygen.

The last aspect of this brief review of laboratory compliance deals with analytical test methods. It is surprising to find an adequately trained laboratory analyst who does not know that test methods must be validated or verified. However, it is also surprising to often find analysts who perform procedures on which they have not been qualified.

Slightly less often, you also find experienced lab personnel who have developed little "tricks" they use in the performance of an analysis. These "tricks" frequently constitute changes to the method that have not been approved by accepted change control procedures or validated to show they have not affected the performance of the method. This occurs with both compendial and noncompendial procedures, and control requires extra scrutiny and diligence on the part of laboratory management. Needless to say, such unauthorized "tricks" are unacceptable and should be forbidden by both policy and procedure.

In summary, control of testing laboratories is a never ending concern. Well run labs have tight and adequate SOPs, good training, effective change control, quality oversight and review, and control of equipment, standards and samples. Operating a laboratory that is in compliance and control is hard work and a continuous challenge. �

Efrem Zaret, Ph.D., president of EZ Associates Inc., consults in GMP compliance and training, quality assurance and control, clinical supplies, logistics, regulatory affairs and product and package development. Reach him at 908-753-8566 or ef@ezassociates.com.