Dissolution testing and good manufacturing practices

April 1, 2007

Missed or late calibration dates can accumulate, and even if the equipment is labelled appropriately, it can suggest poor management of resources and priorities.

Good manufacturing practice (GMP) issues are pervasive in the dissolution testing laboratory because there is so much equipment, documentation and validation involved in testing so many products at different stages of development. Each laboratory has different members of staff working on a variety of analytical instruments and fully automated dissolution testing equipment, all requiring individual log book and calibration, maintenance and operating procedures.

Dissolution testing requires extensive notebook documentation and witnessing, as the dissolution profile test can have numerous data points with observations and pre and post-equipment checks. Training and documentation is becoming more critical in the modern dissolution laboratory where turnover is high and products vary.

(Photos Courtesy of Boston Analytical Inc.)

The array of products tested requires constant validation and revalidation as formulations change, and new test methods are written and revised.

Constant monitoring of GMP adherence is necessary in dissolution testing to ensure compliance and successful audit results. Internal audits must be a regular part of the laboratory operations. Guidelines on how to prepare for a preapproval inspection will also be described in this article.

Equipment

Metrology is very important in the dissolution laboratory. Personnel outside the dissolution and/or analytical group may be involved in tracking equipment identification, repairs and the calibration status of instrumentation. This involves frequent communication between the groups, especially for calibration time deadlines.

Calibrating equipment on time is a good indication of a laboratory's efficiency. Missed or late calibration dates can accumulate, and even if the equipment is labelled appropriately, it can suggest poor management of resources and priorities.

The status of equipment — whether it is out of service for repairs, calibration or under investigation — should be very clearly marked to avoid any ambiguities regarding the equipment's condition and usability. Special circumstances, such as use for only one apparatus or new equipment waiting for validation, should be labelled accordingly.

Log books or any notebooks associated with or assigned to equipment must be current and contain the most useful information; that is, observations of problems and how the problems were remedied; calibration results and failures; corrective action; and routine maintenance and performance checks.

It is assumed that there is a custodian for each piece of equipment and that that person enters the information into the log book. This becomes somewhat cumbersome when someone other than the custodian uses the equipment. Communication is critical and the analyst must know when the equipment has had problems.

An accurate and current logbook can offer insight into the cause of aberrant data and support the repair, replacement or upgrading of equipment.

The operational procedures must be detailed enough so the analyst can use the instrument to obtain accurate results without having to rely on undocumented hints and reminders from more experienced users.

Notebook documentation

There will certainly be an updated standard operating procedure (SOP) for the use and documentation rules for notebooks. The dissolution test lends itself to inserts or templated work sheets, and such practices are very useful for several reasons. The analyst has many things to remember such as rpm; temperature checks (before and after the run); the correct speed and apparatus; sinkers; deaeration; observations; sample and equipment IDs, and sample and reagent preparation. This is only a partial list of all the items that should be recorded.

Key points

A templated list where one fills in the blanks or makes a check mark can keep information organized, which helps the witness tremendously. It also causes the analyst to double-check whether all aspects of the test have been performed properly. The procedure for handling inserts or templated worksheets has to be clearly spelled out in the SOP, and quality assurance (QA) personnel should have complete confidence that the documentation is compliant.

There are other concerns regarding documentation. Consider thermal paper, for example. Some laboratories sign and date the thermal paper, photocopy it, then a witness signs and dates the photocopy. The thermal paper can then be destroyed. Whatever the documentation approach, it should be outlined in the SOP.

The recording of sampling times is the subject of much discussion. Does the analyst record in real-time every pull (using a traceable calibrated timepiece, of course) or do they refer to a test method and presume adherence to the prescribed sampling interval? With manual sampling, this can be labour-intensive, but fortunately, with autosampling, this is alleviated as the instrument printout reveals when the sample was taken.

In the dissolution laboratory where the testing may require multiple users for the same standard solution and/or medium preparation, there may be special notebooks that are used for this purpose only. The specific preparation is entered into the notebook with a date, then as other analysts use the solution or medium, the date and their initials are also entered.

The analyst refers to the multi-user notebook number and page in their write-up of the experiment in their own notebook. The witness must refer to this separate notebook when checking the data. As most notebooks are for single users, the relevant SOP must be amended to enable multi-users.

The role of the witness should not be underestimated. The best witness is an analyst who has previously performed the test and can accurately detect omissions, mistakes and out-of-trend results. The witness, in addition to having in-depth familiarity with the method, should have some training on the witnessing process. A checklist of things to look for would be useful.

Training

In the dissolution laboratory, training can be labour intensive and drain resources, but given that it is scrutinized by regulatory agencies, it must be performed adequately and documented. Training is a two-part issue. One part is to train a new analyst to perform dissolution testing properly, and the other is the training on specific compound test methods.

There is some debate regarding the use of equipment calibration as a training tool. The dissolution tester calibration is a challenging task because of the numerous sources of error that can occur with an untrained person performing the test. Being able to perform the calibration test properly is an indication of proficiency. Difficulties can arise when a trainee performs the actual calibration as a failure would pose problems. The training should be done in tandem with an actual calibration performed by a well-trained analyst.

There are other aspects of training for dissolution testing, for example, observations. In no other analysis are observations so critical. Training in terminology and what to look for during a dissolution test can be extremely useful in explaining aberrant data and exploring the best and most accurate method during method development. Training a new analyst should be assigned to one person and they should keep track of when — and if — all the training elements are fulfilled. When completed, this should be entered into training records that are kept by a system regulated by a training SOP.

Training on a particular method can be looked at in two ways. Some believe an analyst can take a method and perform the test without doing a 'training test'. Others take a more conservative approach and insist on the analyst performing a training sample test that generates similar results obtained by an experienced analyst.

It is probably best to consider the experience level of the second analyst and the difficulty or uniqueness of the test. A project where the test is routine may not need a training test, however, a test that requires detailed observations or complicated sample introduction, suspensions, for example, may need a training test.

Validation

One of the most frequently sighted areas for 483 warning letters is the lack of validation or improper validation. With the frequent use of autosamplers and fully automated systems in the dissolution laboratory, the validation of the test method, using manual versus automation is paramount. Also, the equipment must be validated, keeping in mind the unique performance aspects of the specialized equipment.

There are two parts to this issue. The instrument itself should go through performance checks that are part of the routine operation of the instrument, usually thought of as the operation qualification (OQ). Presumably, the installation qualification (IQ) was performed when the instrument was newly acquired. Once the OQ and IQ are satisfactorily completed validation can be performed using the product.

Validating a simple autosampler may be a straightforward manual and automated run performed concurrently, comparing the results with predetermined acceptance criteria based on the inherent variability of the product. A fully automated system is much more complicated and requires a validation report as part of the validation documentation for filing the compound. Any automated system validation should not overlook contamination from previously tested compounds (cleaning validation) and build-up of surfactant. Dwell times, sample lines and filter checks are often problem areas.

Test methods should reflect the discoveries of a thorough validation. A 'critical factors' section is a major component of the test method. This points out those areas where special attention must be paid to some aspect of the analysis; for example, it may address the standard preparation.

In dissolution testing, the standard may be difficult to dissolve in aqueous medium. Instructions on the proper amount and addition order of a small amount of alcohol may be critical to the proper dissolution of the drug substance. Critical factors for dissolution testing include:

  • The deaeration method.

  • Sinker type and, if handmade, the instructions (i.e., if alcohol was used, sonication time etc).

  • Cleaning instructions for vessels and/or autosamplers.

  • Any special precautions for cleaning autoinjectors when surfactants are used.

  • Special instructions for the rotation of paddles before the test begins (this may be required for suspensions).

  • The exact mixing procedure (for dosage forms that need reconstitution.

  • Typical absorptivity values (UV) or response factors (HPLC) and the precautions required to protect them from light.

Of course, this information is in the method, but a highlighted 'critical factors' section will alert the analyst to unusual test aspects.

Audits

Frequent internal audits help to keep analysts aware of GMP issues. The internal audit by the dissolution laboratory personnel is an effective way to monitor GMP and serves as a training tool for the analyst doing the monitoring. It forces them to consider their own work habits and it is less threatening for the other analysts to have observations come from colleagues rather than outside personnel.

This can be done routinely as a part of objectives or performance standards. A checklist is an important aid to this process. The auditor should immediately inform the group of their findings, thereby enabling the offenders to rectify the problem under their own initiative.

One area that should be routinely inspected in the dissolution laboratory is sources of vibration, especially external vibration. The counter tops should be examined to see if the dissolution bath is in close proximity to shakers, hoods or centrifuges. Local construction is a source of vibration and can be overlooked.

It is also useful to observe if there is heavy foot traffic, or opening and slamming of doors nearby. Making vibration a part of the audit checklist is highly recommended.

Other internal audits are performed by QA and/or by teams of section analysts. Frequent, routine audits are necessary to assure adherence to GMPs.

Preapproval inspection preparation

In the dissolution area, the preparations for a preapproval inspection involve four major facets:

  • Rewitnessing the notebook documentation.

  • Reviewing all reports and training records.

  • Following a sample from when it was received from the stability chambers to its disposal.

  • Performing a mock preapproval inspection.

All the product lots included in the filing should be identified. The notebooks that included the testing of those lots should also be collected. Entries related to these lots should be rewitnessed, but not by the original witness. All laboratory information management systems (LIMS) reports should also be checked for accuracy.

The exercise of following a sample on its journey from the stability chamber to final disposal, though laborious, is worthwhile as many systems are checked in the process Other than the notebook, equipment log book should be reviewed.

It is also useful to check the calibration tracking system. The documentation trail of how the sample was received and where the sample was stored after leaving the chamber can then be examined. After the testing is completed, the method of sample retention can be reviewed.

Other documents, such as method transfer reports, validation reports, SOPs and out-of-specification reports were examined for several attributes:

  • Are they in final form?

  • Was any corrective action taken and was it written up?

  • Was there a transcription check?

  • Were automated systems validation written up in a separate section or report?

It is very useful if QA and senior analysts or managers in another section perform a mock preapproval inspection. The results of this should be written in a report, including how to address any problems.

Conclusions

The subject of GMP is vast and this article has focused on dissolution testing. The issues highlighted here are items that have previously been debated or have attracted special attention from inspectors.

Each laboratory should evaluate the level of GMP compliance for dissolution testing and identify areas of strength and weakness. The routine involvement of the bench chemist can be very productive for the inspection of dissolution laboratory operations.

Vivian A. Gray is a president at V.A. Gray Consulting Inc. (USA).