Most of the 483s and warning letters are issued because of common GMP errors. Below I have described common mistakes (and ways to avoid them) that I have seen and that many managers, supervisors, and executives have told me they have seen. Many common good manufacturing practice errors in pharmaceuticals can be easily avoided by following a few simple rules.
Safety First, Last, and Always
We all must observe safety rules, for our own safety and to protect the product from contamination. We work with ultramodern equipment, in laboratories and facilities that cost millions of dollars, and with exciting technology, nevertheless, some of the products and materials we work with are potently biohazardous. Electricity running through some pieces of equipment also presents a risk. Guards, such as on packaging equipment, are there for a reason.
I always tell employees to locate eyewashes, fire extinguishers, and equipment "emergency stop" buttons, learn your company's evacuation procedures. If you clean or do maintenance on vessels, tanks, steam lines, or lyophilizers, learn the appropriate safety precautions and follow them thoroughly. That includes company policy regarding work orders and lockout and tag out procedures to ensure that the equipment is not in use before you begin maintenance.
1. Wear personal protective equipment: one common GMP mistake is not wearing your safety glasses. Your eyes are too precious not to protect them. Always wear your safety glasses, safety shoes, respirators, and other personal protective equipment. Take the time to think things through. Stay alert, and trust your instincts. Avoid situations that look potentially dangerous, and let your supervisors or others know. Read the Material Safety Data Sheets (MSDS) for all materials that you work with.
2. Read and observe all labels and signs. I once saw an experienced operator suspect that a vendor had changed the process on a raw material because the label "looked different" Read all labels and signs carefully. Check for "released" stickers. Ensure that the material has not expired and that it is the correct material. Caution and warning signs in your plant should be printed in all languages spoken in the plant.
3. Be especially careful around breaks, when you are tired, called away, and so on. GMP regulation and safety violations occur most often right before break times, before lunch, before your shift is over when it's time to go home, when someone interrupts you or breaks your train of thought, and so on. Be especially vigilant during those times. The most common injuries in our business seem to be hand and back injuries, so use proper lifting techniques, slow down, and think about what you are about to do before putting your hands or back at risk.
4. Wear only appropriate clothing. In most companies, supervisors are responsible for providing on-the-job training (including training in proper attire, such as sterile gowning) and then monitoring employees to make sure that they are wearing appropriate clothing. One common GMP error is not wearing your lab coat while you are in the laboratory (or visitors or contractors not wearing hair coverings, shoe coverings, lab coats, and so on). Splashes can be dangerous and can ruin your clothes. When visiting bulk chemical plants, don't wear designer suits or shoes.
Another common error is wearing your lab coat or plant uniform outside the building. Some 483 observations noted that employees were smoking outside of buildings while wearing their plant uniforms. Some types of jewelry are not allowed in certain areas. Check with your supervisor if you're not sure.
5. Keep surfaces and equipment clean. Follow approved cleaning procedures, and use approved cleaning solutions, People have become sick and in the most serious case that I'm aware of, have died — because cleaning was inadequate, and the cleaning process had never been validated. One of the first things that investigators or visitors notice when they visit your plant is the facility's general cleanliness. Don't stack cardboard boxes in the hallways. Before you use a piece of equipment, ensure that it was cleaned by checking the "Cleaned Equipment" tag or the equipment logbook. If possible, open the equipment and look inside to make sure that no rinse water was accidentally left behind.
6. Wash your hands. Most pharmaceutical plants have signs in the bathrooms reminding employees to wash their hands before returning to the plant. If you've ever put your hand on a plate and cultured the bacteria present, you know that bacteria are everywhere, in large quantities, although omnipresent in life, they are not something that any one of us wants in our medicines or injectables.
7. Report an Illness. I know of no other industry-other than food - that requires personnel working over the open product to notify their supervisors when they have a cold it is a GMP requirement that employees and temporary employees do this. On those days when you're not feeling up to par, you can be assigned to attend GMP classes, revise SOPs, or catch up on your scintillating GMP reading, such as articles like this one.
8. Use only released raw materials, packaging components, and labels. Use no expired materials. Under cGMPs, only released materials can be used in all clinical and commercial lots of product. A common error is to store expired materials with current materials. Remove, segregate, and/or destroy all expired materials.
9. Think. Even though the pace in our industry is fast, and everyone has more to do than they can possibly get done, everyone deserves the time to think things through.
Every time I have allowed myself to be rushed, I have made a critical mistake.
10. Always fill in the blanks. Record all requested information. If it is truly not applicable, write N/A; your initials, and the date. If pages or sections of forms are not applicable, line through them, write N/A, your initials, and the date. The correct information must be entered on batch records, equipment logbooks, and test result forms, otherwise, your QA department will be checking with you soon to find out why you didn't complete the work.
11. Record results as you get them. One common GMP error is to speed through documents at the end of the day or at the end of your shift, filling in all the blanks at one time. But we all know that it is impossible to remember what we did five minutes ago, much less eight hours ago. You have to train yourself and your people to record results and information as you get it - on batch records, lab notebooks, and test result forms.
12. Use Indelible Ink. The industry standard is black indelible ink because it photocopies well and does not smear. The pencil is unacceptable because it smears easily and can be erased.
13. Banish the correction fluid. Using correction fluid is not allowed. I know of some employees who don't even have correction fluid in their desk drawers, to avoid the temptation to use it.
14. The line through, Initial, and date all changes. The correct way to make a change is to line with the error once using your indelible ink pen, clearly write the correction above or beside it, and initial and date the correction.
15. Never backdate or falsify records. Always use today's date when documenting your work. If you do not, you are falsifying records. For example, if I made a batch of a product today, and did not fill out a line on a batch record, a QA employee would stop by and ask me whether I had completed that step.
If I did remember completing it, I would write in the Comments section of the document that QA had noticed that I had failed to document the step and that I had in fact completed it. I would initial and date my comment the day that I was writing it. Preferably, I would have an attachment or some sort of corroborating data to back this up! The better idea is to record data when you get it. Under no circumstances should you go back into a batch record and fill it out as though you had filled it out properly, to begin with.
16. There is no such thing as a dumb question. Better to ask and get an answer than to assume and risk a batch, someone recently told me that a single gram of one of their active ingredients was worth $8,000. Some larger biotech companies with products on the market have batches worth $4-7 million each. An awful lot of money is riding on those batches, not to mention the safety, purity, and effectiveness of the products. It's critical that supervisors make sure their people feel comfortable asking those questions and admitting their mistakes.
17. Take action to make things better. In all of the classes I teach, I always ask people to take action to make things better.
Each of us sees things in our day-to-day jobs that others do not. Or we may reach a conclusion faster than someone else. Have the courage to bring up things that need to be improved. Be the responsible employee who picks the piece of paper from the floor rather than steps over it.
As you move up in your career, people are going to trust you with information that is confidential and sensitive. You must honor their confidence but also take action. For example, if employees confide in you that they are worried about the safety of their work area, you must immediately inform the area manager and also your Environmental Health & Safety department coordinator in writing. The point is to not assume that the charge is correct but to turn it over to people who can follow up.
18. Ensure that equipment Is calibrated before using it. Equipment that must be calibrated in a manufacturing or laboratory environment typically has an equipment calibration tag on its front, side, or back that indicates the date the equipment was last calibrated, who did the calibration, and when the next calibration is due. Check to make sure that your equipment is within calibration before you use it. Otherwise, your results or measurements could be inaccurate.
19. Record ID, part, lot, document, revision, and other control numbers. When something goes wrong with a product lot, trying to determine the true source of the problem is often like solving a mystery. The GMPs require that you assign and use unique numbers on each lot of your raw materials, reagents, documents, and all lots of produced products to permit traceability should there ever be a problem.
So when filling out a batch record or recording your results, record equipment, lot, sample, reference sample, and document and revision numbers.
20. Do not bring food, gum, tobacco, or house plants into production and laboratory areas. A common GMP error is bringing drinks into a laboratory. Smoking, eating, and drinking is prohibited in a GMP facility. You do not want to have food inside a GMP facility because rodents and other pests will try to enter the f facility to get the food. A beetle can bore through 0.125 inches of solid plastic to get to food or the glucose or sucrose stored on pallets in your warehouse. Houseplants may have insects on their soil and leaves.
21. Check your pest control devices frequently. If you use an outside pest control service, test it by placing a plastic mouse in one of the traps. If the service doesn't find it, it's not doing a thorough job inspecting and cleaning the traps. Because rats like to run along walls - they do not see well, and they feel safer against a wall - rodent traps should be placed along walls. Clean the bottom tray of insect electrocutors frequently. You may have an insect infestation in the bottom of the tray. If a pregnant female is electrocuted, her young may survive to feed on the remains of the dead insects inside the tray.
22. Before signing anything, check for accuracy, for completeness, and correct calculations. In our industry, a signature is a legal and an ethical responsibility. If you have signature authority and are asked to sign something, you must, to the best of your ability, review it thoroughly and completely, make sure that everything that needs to be attached is attached, and make sure that all calculations are correct. Never sign something without thoroughly reviewing it first. Never sign something that you know to be wrong. Get it corrected and then sign it.
23. Print clearly in logs, and fill them out completely. Fill out all logs and other documents completely. Your handwriting must be clear and legible. If your handwriting, like mine, is difficult to read, then print.
24. Record data directly in the appropriate form or notebook. Do not write original data on scrap paper, napkins, or paper towels and then transfer the information to the appropriate form or notebook. If you accidentally record your data on a piece of scrap paper, staple it to the form or notebook, because it is original data. Always attach printouts and labels where indicated. Never throw away original data.
25. Never simply average out-of-specification results to obtain a passing result do not continue testing samples until you get enough that pass. As a result of the Barr case, there has been a lot of scrutiny in this area. Every company should have an SOP that discusses how to handle out-of-specification results and how to handle failure investigations. One executive recently told me that he suspects that analysts were not telling their supervisor when they got an out-of-specification result because an investigation would have to be done. Supervisors take note: Encourage your people to tell you when they get an unusual result and don't punish them when they do.
26. Have another person perform double checks as Indicated In the batch record. Double checks are required for critical steps, like weighing and adding raw materials, because people have discovered that historically those are problematic areas. A double check means that one person performs the work while another person observes and makes any suggestions or corrections. Individuals then sign or initial the batch record where indicated. GMPs require that you have sufficient staff to do this.
27. Keep shipping, receiving, and other doors closed. A common error is to leave shipping and receiving doors open after a delivery has arrived - an open invitation for pests of all kinds. Owls, snakes, rats, and mice have been found in warehouses looking for food, water, and shelter. A field mouse only needs 0.25 inch to get under a door, so check the bottom of your outside doors. If there is a gap, you could be inviting a rodent problem. Many years ago a mouse ran across the back of a room in an older office building where I was teaching a GMP class. (He probably wanted to make sure he met his GMP training requirement.) The cGMPs require that you have an effective pest control program; keeping your receiving doors closed will help.
28. During an Inspection, answer all questions honestly and directly. Do not guess or speculate. Do not volunteer information. Refer questions that you cannot answer to your supervisor. FDA and other regulatory agencies know that this is how employees are trained. Don't be evasive, and don’t try to hide the truth. Don't guess, and don't state your opinion. "If you think we're bad, you should see those guys down the hall!"
29. Report mistakes - or suspected mistakes - as soon as possible to your supervisor. I hate to make mistakes, rather be perfect. But the truth is that we're all human, and human beings make mistakes. As a supervisor, encourage your people to tell you things. Don’t jump all over them when they do so they never do it again. And don't go looking for scapegoats. If something goes wrong in your group, you as a supervisor or manager must accept responsibility for the mistake see what you can reconstruct or recover, and figure out how you can prevent the mistake from happening again.
30. Read and become familiar with all SOPs and other documents that relate to your work. You must know your SOPs. A common 483 observation continues to be "Firm failed to follow its own SOP." If an SOP needs to be revised, tell your supervisor and offer to help revise it and get it approved.
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