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Questions and Answers on
Current Good Manufacturing Practices, Control
of Components and Drug
1. Do the CGMP regulations permit the destruction of an internal quality assurance audit report once the corrective action has been completed? The CGMP regulations (21 CFR 210 and 211) for finished pharmaceutical manufacturing do not specifically address the requirement to conduct, or to keep records of, internal quality assurance audits. If the report in question were from a routine audit to verify that the firm's quality system is operating as intended, then it would be acceptable if the firm elected to discard the report once all corrections have been verified. However, any documentation of corrective action as a result of such an audit would have to be retained (see 211.180 and 211.188). For example, if a routine internal audit finds a problem with a mixing step and the outcome is a change in mixing time, all affected procedures, including the master production record, are to reflect the necessary changes, and such records are subject to FDA inspection as usual. Any investigation into the impact this problem had on related batches is to be retained and also made available for inspection by FDA (see 211.192). In addition, any reports of investigations or evaluations prepared in response to, for example, a product complaint (211.198), vendor qualification (211.84), periodic review of records and data (211.180(e)), and a failure investigation (211.192) are not internal audits as discussed above. Such records are subject to FDA inspection and must be retained for at least the time specified in the CGMP regulations (see 211.180). References:
Contact for further information:
Rosa Motta, CDER 2. Can containers, closures, and packaging materials be sampled for receipt examination in the warehouse? Yes. Generally, we believe that sampling in a typical drug manufacturing facility warehouse would not represent a risk to the container/closure or affect the integrity of the sample results. But whether the act of collecting a sample in the warehouse violates the CGMPs requirement that containers "be opened, sampled, and sealed in a manner designed to prevent contamination of their contents..." will depend on the purported quality characteristics of the material under sample and the warehouse environment. For container/closures purporting to be sterile or depyrogenated, sampling should be under conditions equivalent to the purported quality of the material: a warehouse environment would not suffice (see 211.94 and 211.113(b)). This is to preserve the fitness for use of the remaining container/closures as well as ensure sample integrity, if they are to be examined for microbial contamination. At a minimum, any sampling should be performed in a manner to limit exposure to the environment during and after the time samples are removed (i.e., wiping outside surfaces, limiting time that the original package is open, and properly resealing original package). Well-written and followed procedures are the critical elements. Note that the CGMPs at 211.84 permit a manufacturer to release for use a shipment of containers/closures based on the supplier's certificate of analysis and a visual identification of the containers/closures. Once a supplier's reliability has been established by validation of their test results, a manufacturer could perform the visual examination entirely in the warehouse. References:
Contact for further information:
Anthony Charity, CDER 3. A firm has multiple media fill failures. They conducted their media fills using TSB (tryptic soy broth) prepared by filtration through 0.2 micron sterilizing filter. Investigation did not show any obvious causes. What could be the source of contamination? A firm recently had multiple media fill failures. The media fill runs, simulating the filling process during production, were conducted inside an isolator. The firm used TSB (non-sterile bulk powder) from a commercial source, and prepared the sterile solution by filtering through a 0.2 micron sterilizing filter. An investigation was launched to trace the source of contamination. The investigation was not successful in isolating or recovering the contaminating organism using conventional microbiological techniques, including the use of selective (e.g., blood agar) and nonselective (e.g., TSB and tryptic soy agar) media, and examination under a microscope. The contaminant was eventually identified to be Acholeplasma laidlawii by using 16S rRNA gene sequence. The firm subsequently conducted studies to confirm the presence of Acholeplasma laidlawii in the lot of TSB used. Therefore, it was not a contaminant from the process, but from the media source. Acholeplasma laidlawii belongs to an order of mycoplasma. Mycoplasma contain only a cell membrane and have no cell wall. They are not susceptible to beta-lactams and do not take up Gram stain. Individual organisms are pleomorphic (assume various shape from cocci to rods to filaments), varying in size from 0.2 to 0.3 microns or smaller. It has been shown that Acholeplasma laidlawii is capable of penetrating a 0.2 micron filter, but is retained by a 0.1 micron filter (see Sundaram, et al.). Acholeplasma laidlawii is known to be associated with animal-derived material, and microbiological media is often from animal sources. Environmental monitoring of mycoplasma requires selective media (PPLO broth or agar). Resolution: For now, this firm has decided to filter prepared TSB, for use in media fills, through a 0.1 micron filter (note: we do not expect or require firms to routinely use 0.1 micron filters for media preparation). In the future, the firm will use sterile, irradiated TSB when it becomes available from a commercial supplier. (Firm's autoclave is too small to permit processing of TSB for media fills, so this was not a viable option.) The firm will continue monitoring for mycoplasma and has revalidated their cleaning procedure to verify its removal. In this case, a thorough investigation by the firm led to a determination of the cause of the failure and an appropriate corrective action. References:
Contact for further information:
Brenda Uratani, CDER 4. How many containers of each component from each shipment must a firm sample and test to comply with the CGMP requirements for identity testing? Do the CGMPs permit the identity test on a pooled, or composite, sample of multiple containers? The Current Good Manufacturing Practice (CGMP) regulations address component sampling and testing primarily at 21 CFR 211.84. These regulations require representative samples of each shipment of each lot of active and inactive component (or raw materials) to be tested to confirm the identity of the component as labeled prior to release for use in drug product manufacturing. The regulations acknowledge that more than one test may be needed to ascertain a component’s identity. For the purpose of this answer, a component’s identity is its chemical structure and its physical form (e.g., polymorph, solvate, and appearance) including, if appropriate, its stereochemistry or immunochemistry. (See also ICH Q6A The CGMP regulations do not specify the number of containers to be sampled from each received shipment. However, 21 CFR 211.84(b) establishes the principles to be followed in designing a sampling program for components. The requirements of this section can be summarized as follows:
The first three are most relevant to the question of how many containers to sample for identity testing, i.e., representative sampling, tolerance for variability and confidence required, and past history. (The amount needed for analysis and reserve can be readily met by sampling even one container, so the number of containers is not an important issue once the shipment’s identity is verified.) Unlike most component attributes, a component’s identity is generally a discrete variable, i.e., the material in the container either is or is not what the label purports it to be. The component container’s content might differ from what the container label states due to mistakes in filling and labeling by the supplier or repacker, or as a result of the substitution of a container’s contents during distribution and warehousing before receipt by the drug product manufacturer. Using a wrong component in processing could result in a serious public health hazard. For these reasons, manufacturers need to develop an approach that provides a high degree of confidence that each container in each shipment contains the material purported by the label. (See also 21 CFR 211.160(b), which requires all sampling to be representative and scientifically sound.) The approach must account for the fact that the material’s identity must not vary from what is specified. The past quality history of a supplier and the scope of their operations is relevant to the chance for mistakes to occur under a supplier’s control, but does not necessarily bear on what happens to a drug once it is outside the supplier’s control. How many containers of each component from each shipment must a firm sample and test to comply with the CGMP requirements for identity testing? The regulation at 21 CFR 211.84 requires that representative samples of each shipment of each lot shall be collected for testing. Some manufacturers have interpreted the CGMPs to require that each container in a shipment be sampled and tested for the attribute of identity. Testing samples from every container to determine identity may be valuable particularly for components purchased from distributors. (Analytical equipment and methods are readily available that permit rapid, non-destructive identification of material directly in containers in a warehouse area.) The CGMPs permit each drug product manufacturer to make its own decision as to the number of containers to sample, as long as the sampling plan is scientifically sound, leads to representative samples, and complies with the principles established at 21 CFR 211.84(b). An important caveat applies with respect to 21 CFR 211.84: samples are to be taken by the drug product manufacturer from containers after receipt (i.e., pre-shipment samples or so-called “piggyback” samples are generally not acceptable). Do the CGMPs permit the identity test on a pooled, or composite, sample of multiple containers? The CGMPs address the issue of sample compositing directly but only in the context of individual container sampling. Section 21 CFR 211.84(c)(4) explicitly prohibits compositing samples taken from the top, middle, and bottom of a single container when such stratified sampling is considered necessary (as might be the case when moisture content needs to be controlled, particularly when only a portion of a container may be used in a drug product batch). The preamble for 21 CFR 211.84(c)(4) explains further that there "is no general prohibition... on compositing samples [from single containers] where such compositing would not mask subdivisions of the sample that do not meet specifications" (see 1978 preamble, par. 231). Testing individual samples from multiple containers provides a high level of assurance and is consistent with CGMP. Testing a composite sample for identity could satisfy the CGMP regulations (21 CFR 211.84 and 21 CFR 211.160) but only if a manufacturer demonstrates either that the detection of a single non-conforming container is not masked by compositing or that an additional test(s) routinely performed on the composite sample assures that all containers sampled contain the same material. Thus, a purity assay on a composite sample prepared by mixing equal aliquots from each container may be acceptable provided such a test is sufficiently sensitive to reveal the presence of a single non-conforming container. References:
Contact for further information: Brian Hasselbalch, CDER Steven Wolfgang, Ph.D., CDER
Date created: August 4, 2004, updated October 25, 2007 |
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