An audit is nothing more than an evaluation of conformance to a particular standard or set of standards. For the pharmaceutical laboratory, this could include conforming to current Good Manufacturing Practices (21 CFR 211), Drug Enforcement Agency (DEA) requirements for handling of controlled substances or the OSHA laboratory standards or customer requirements.
Audits that a pharmaceutical laboratory should expect on a regular basis are those conducted by regulatory bodies such as FDA and those conducted by customers.
In addition, periodic internal audits should be performed to foster self-improvement and to identify and correct any problems before they are discovered through FDA or customer audits. Also, it is extremely useful to have a third-party audit of your facility done yearly. A number of independent consultants conduct such audits, usually in the format of a mock FDA inspection, thus providing a view of laboratory operations from the perspective of an unbiased outsider.
Since most audits are done with little or no notice, it is necessary for the pharmaceutical laboratory to be in substantial compliance with cGMPs at all times. The whole point of no-notice audits, such as FDA inspections, is to ensure that laboratories are compliant with cGMPs at all times. Telling the FDA that "you caught me on a bad day," just doesn't work. Most regulatory audits of an analytical laboratory will examine items such as instrument calibration, documentation practices, handling of out-of-specification results, raw data, such as chromato-grams, traceability of data, training records, handling and audits of data, standard operating procedures (SOPs), change control, validations and laboratory log books.
Instrument Calibration/Qualification
All laboratory instruments need to be qualified on a regular basis. I prefer the term qualify to calibrate, as calibration involves making adjustments to an instrument, whereas qualification is verification of proper performance.
For each instrument to be qualified there should be an SOP that describes the qualification procedure that includes acceptance criteria as well as actions to be taken if the qualification fails. Each instrument should have a sticker affixed to it that states at a minimum the qualification date, SOP reference, notebook reference and requalification date.
If an instrument's qualification has expired, label it "OUT OF CALIBRATION-DO NOT USE." Such a label takes the instrument "out of the inspection," and makes sure that no cGMP work is performed, or has been performed on that instrument during the time that it is out of calibration.
The nature or extent of a qualification will of course depend upon the equipment involved. HPLCs, for example, might be qualified twice a year, whereas an infrared spectrophotometer might be qualified weekly. In addition, HPLC equipment that consist of multiple components such as solvent delivery systems, autosamplers and detectors, will need to have each component separately qualified, as opposed to the daily system suitability test that looks at the components together as a system.
Documentation Practices, Handling OOS Results and Raw Data
Documentation is probably the single most important aspect in the pharmaceutical laboratory. As the saying goes, "if you didn't write it down, you didn't do it."
Every procedure or activity that involves generation of data must be fully documented, preferably in a hard-bound notebook with sequentially numbered pages, using indelible ink. If worksheets are used, they should be issued in a controlled manner, preferably by computer, using software that is compliant with 21 CFR Part 11. Errors should be corrected in a manner that shows the crossed-out error along with corrected information that is initialed and dated.
Handling of out of specification (OOS) results has been, and is still, a hot item. Regulatory audits will always look at how a laboratory handles OOS results. The laboratory must have a mechanism for OOS investigation that strives to find its cause, and that specifies what action or actions are to be taken as a result of that investigation. Improper handling of OOS is a deficiency often cited on FDA 483 reports and can be avoided by having a sensible, written OOS investigation procedure. FDA has a guidance document dealing with OOS investigations that is very instructive for those who need to develop a sound OOS investigation policy.
Raw data should be recorded directly into a hardbound notebook, in real-time, as the work is being performed, not on notepads or loose papers and then transcribed later. These should include, at minimum, dates, description of the method, for standard methods such as USP/NF, and a reference to the procedure being used such as: • weights; • titration values; • preparation of standards, samples and mobile phase; • all calculations; • cross-references to chromatograms, spectra and other instrument printouts; • lot numbers of standards and samples; • reference to preparation and standardization of solutions and reagents; • explanation of any corrections; • results; and • signatures of author and reviewer.
SOPs and Change Control
There should be an approved SOP in place for every laboratory operation. Typical laboratory SOPs include how to write an SOP; creation of SOPs and change control training; instrument operation and calibration procedures; analytical method monographs; sampling receiving, testing, and disposition of raw materials, in-process materials and finished products; analytical methods validation and use of analytical standards; preparation and standardization of volumetric solutions; specifications and validation; laboratory log book procedures; handling of tests, indicator and buffer solutions and dry chemicals; reserve samples and records; failure investigations; standard practices for chromatography; storage and expiration of stock standard solutions; shelf life determination of stock standards; laboratory training programs; notebook maintenance; audit of outside laboratories; and documentation practices.
A system must be in place for generating and modifying SOPs that includes a review and approval of each new or revised SOP. The system must also ensure that only the most recent version of an SOP is in use and that all older versions are appropriately archived, and should include a change history that explains the justification for each change.
Validations
The pharmaceutical laboratory must use validated methods for all analytical work. A method is generally entitled to validity if it is a USP/NF method, except for stability samples; it is part of an approved drug submission (NDA or ANDA for example); and it has been actually validated by the laboratory.
The USP and the International Conference on Harmonization both provide guidance for analytical method validation. A typical method validation for an assay will include linearity and range, accuracy, precision, limit of detection, limit of quantitation and robustness.
In addition, for stability work, forced degradation studies may be needed that include acid and base hydrolysis, oxidation and light and heat degradation. A typical auditor will examine the validation protocol, validation report and all associated raw data.
Laboratory Log Books
There should be a hard-bound log book for signing samples into the laboratory. The entries should include date, name and lot number of sample, packaging size and the signature of the submitter.
Some log books even include the names of tests that are required. When a sample has been completed and the results published, an entry should be made in the log book stating the date completed and initialed by a laboratory analyst or supervisor.
Log books are very important and are always examined by auditors, particularly during FDA inspections. A sample log book is an excellent way to verify sequencing, to see if a sample was signed in before it was tested and was released after testing was completed.
From a broader manufacturing standpoint, the log book can show that samples were taken after manufacture of product or that a raw material was tested prior to being used to manufacture the product.
The key to a good audit is to have a sound laboratory cGMP program in place and to follow it judiciously in order to ensure a regular and ongoing state of compliance. A third party auditor, in addition to providing an objective look at your laboratory, can also assist in developing or improving your laboratory's cGMP program. n
Clifford L. Nilsen is former owner and president of Lycoming Analytical Laboratories. He has 35 years of industry experience in solving management, technical and regulatory problems in the analytical laboratory. He is currently a full-time consultant to the pharmaceutical and nutraceutical industries. Reach him at 570-477-5042 |
