Common Misconceptions About Raw Materials in GMP Facilities - A Compilation of Important Questions and Expert Answers
There are a number of misconceptions about the usage and specifiB,cally, qualiB,fication processes of raw materials in GMP facilities. Professionals working in these facilities very often are unsure of what exactly constitutes raw materials, the importance of these materials and the role they play and what the FDA expects to be done to comply with regulatory requirements.
On this webpage, is a compilation of important questions asked by ComplianceOnline users and answered by experts. It is noted that in a GMP facility, anything and everything could affect the quality of the finished product. The quality of something as mundane as a glove used for testing or the machine that is used for printing labels to something as complex as a critical Active Pharmaceutical Ingredient can compromise the quality of the final product and lead to the FDA issuing citations to your facility for substandard raw materials used.
Below are some of the common misconceptions on raw materials in GMP facilities with clarification from experts:
Q1. Is it true that 80% of all FDA findings are raw material related?
Yes - almost 4 out 5 FDA warning letters cite raw material deficiencies. There are other deficiencies noted as well, but this is a common element in 80 % of the warning letters and Form 483s issued by the FDA. This means that the FDA found raw material issues in 4 out of 5 cases. Therefore, raw material issues are very common across FDA regulated industries.
Q2. Is there a guideline on when to perform Supplier/Raw Material Qualification during the various Clinical Phases? Is qualification required in early Clinical Phases?
The guidelines to be used are GMP guidelines. These are applicable from Phase 2 onwards. For Phase 1 products, certain flexibility is allowed on GMP. For very early stages, it is not necessary to follow GMP. Raw material qualification can be deferred to Phase 2. Specifications and criteria for raw materials should be defined as early as possible so that issues don't crop up later. So the simple answer is that raw material qualification would have to be done around the Phase 2, A Stage and the recommendation is to do it as soon as is reasonably possible.
Q3.At which phase of drug development is a manufacturer required to have Supplier Qualification and Raw Material Qualification Programs in place?
These should be in place before manufacturing starts and before the first clinical trials commence. Ideally speaking, even if pre-clinical testing is done, you definitely want to make sure that the material being tested in animal studies is similar to the clinical material. Therefore, raw material and supplier qualification should be defined around the R&D stage of the product. Manufacturers are allowed to use a small, pilot scale material for the initial pre-clinical studies and the initial R&D, but they run the risk of not being able to find a raw material provider at a later stage. If the qualification criteria used in the initial stages are too stringent or too loose, there might be issues later. It is better that the moment you're done with the R&D stage of the product, it is the time to start thinking about raw material qualification so that you don't run into problems later.
Q4. Do materials such as gloves, printer ribbons, stir bars, and autoclave wrap warrant raw material controls such as specifications and vendor/material qualification or is this overkill?
If your printer ribbons are used for printing your labels, then you'd definitely want to make sure that your printer ribbons are of good quality. Let us say that in your manufacturing facility, you are supposed to print 1,000 labels. But your ribbon is of substandard quality so it dries out after the 900th label is printed. This would result in extra labels that are not printed properly, resulting them in being Out of Specification. This would lead to issues and situations where you have to explain why 1,000 labels had to be re-printed and so on.
These would have to be taken as a case by case. Let us take gloves as an example. If your gloves were contaminated or they have holes in it or of such bad quality that they tear easily - these kinds of issues could affect your testing. You would think gloves are something that you do not have to worry about but think of this situation: you're using gloves for doing QC testing in the sterile suite in a vaccine facility. The gloves however are contaminated and you're using them in a sterile place and your entire QC suite is contaminated. These kinds of situations can drastically affect the quality of a product. So, it might look like materials such as gloves do not need qualification, but they can lead to situations like the one described. Therefore, you have to take it on a case-by-case basis, ensuring that any material that affects the quality of the finished product has specifications and that they meet them.
Q5. What is meant by QC SOP defined time-line?
The QC SOP should have a timeline at which raw materials have to be tested. Sometimes, if the material is perishable or has a shorter shelf-life, it might have to be used within a few days or within a few hours of getting it. This is particularly true for biological products. The SOP therefore would define the material from the time of receipt to its testing within three days of receipt. This is what's meant by a QC SOP timeline. Every test that is conducted on the raw material should have a timeline and it has to be demonstrated in the batch record that the test was done within the specified timeline.
Q6. When it comes to biologics, testing 10 lots seems a bit too much - Are there any guidelines on how many lots to test during the raw material qualification process?
The media used for biological material such as the components of growth media - tubes, flasks and systems used to grow - can be bought as 10 lots. In such cases, it is best to buy 10 lots if it is possible. If not, then a reasonable justification has to be given. But if the FDA finds the justification is not strong enough - if they say that certain material can be bought as 10 lots - then it would reflect badly on the facility. So, it would be best to do the maximum wherever possible.
Q7. When investigating Out of Specification, does damage and measurements specific to testing have to be included?
Out of Specification would include anything. It could even include packaging. For example, if you were supposed to get a package in a crate and the side is torn or it is too dusty or has other abnormalities, then that would be an Out of Specification. The vendor is supposed to provide material of certain quality and if it's not meeting those specifications, then this should obviously be investigated. So Out of Specification does include damage and measurements. Let us take labels as an example. The providers are supposed to give you 10,000 labels, but on counting you find that there are actually 10,100 or 10,099. So, there is a variation in the specified number and you have to make sure why there are variations. If any material that you get is Out of Specification, then it should be investigated.
Q8. Chemicals for testing in-process and lot release product are considered manufacturing aides - therefore do they have to be qualified and released before use?
Yes. As these are testing materials and if your testing is faulty, throwing up results that you cannot trust, then you will have multiple issues for all wrong reasons. You certainly want to make sure that any material you use for testing is of a quality that you need. Take a hypothetical situation where your QC lab disqualifies a particular lot. Later, you find out that the reagents or machines or tubes they used were substandard, then the lot would have to be re-tested and show that it was okay to begin with.
A warning letter was issued by the FDA to a company that found an Out of Specification. The QA lab had determined that the QC lab was using a reagent that had expired and that is why the material was found to be Out of Specification. The lot had to be retested and was found to be within specification. The FDA found that the material was okay, but the testing was faulty and issued the company a warning letter. So, these things do happen and you certainly want to show that you don't suffer because of them.
So yes, you should show that every material, even the material you use for testing - testing aids that you use - meet specifications and the quality that you expect of them.
Q9. Do gaskets or hose materials need release specification prior to use?
You have to use what is reasonable for your product - so use common sense. When it comes to materials such as this, ask yourself: Do these affect your product's quality? Are these gaskets part of the autoclaving system used to sterilize your tubes or your materials? If yes, then obviously these gaskets are very important so you do have to make sure that they maintain the integrity of your autoclave. Or if these gaskets are necessary to maintain positive air pressure, which requires you to have gaskets of certain quality, then obviously you have to make sure that your gaskets meet those quality specifications.
These questions cover just a fraction of the issues faced by GMP facilities when it comes to qualification of raw materials. To gain a better understanding of the topic, you might consider purchasing the following ComplianceOnline webinars.
Raw Materials in Pharma/Biotech Production
GMP Raw Materials Program Risk Management
Understanding the Current FDA Requirements for Raw Materials and Components
Raw Material Requirements (Health Canada/USP/EP) in a cGMP Environment - Issues and Solutions
