Q1. Do the CGMP regulations require a firm to retain the equipment status identification labels with the batch record or other file?
The CGMP regulations for finished pharmaceuticals require the retention of cleaning and use logs for non-dedicated equipment.
But no similar requirement exists for retaining what are intended to be quick reference or temporary status labels. Examples of these kinds of status labels include: mixing lot 01 of 02; clean, ready for use; and/or not clean.
Q2. Can containers, closures, and packaging materials be sampled for receipt examination in the warehouse?
Yes. Generally sampling in a typical drug manufacturing facility warehouse would not represent a risk to the container or closure or affect the integrity of the sample results. Well-written and followed procedures are the critical elements.
Note that the CGMP regulations at 21 CFR 211.84 permit a manufacturer to release for use a shipment of containers or closures based on the supplier’s certificate of analysis and a visual identification of the containers or 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.
Q3. 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 § 211.84 requires that representative samples of each shipment of each lot shall be collected for testing. Some manufacturers have interpreted the CGMP regulations 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, nondestructive identification of material directly in containers in a warehouse area.)
The CGMP regulations 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 § 211.84(b)
Q4. A firm has multiple media fill failures. They conducted their media fills using TSB (tryptic soy broth) prepared by filtration through a 0.2 micron sterilizing filter. Investigation did not show any obvious causes. What could be 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.
Some products, such as transdermal patches, are made using manufacturing processes with higher in-process material reject rates than for other products and processes. Is this okay?
Maybe. It depends on the cause and consistency of the reject rate. Many transdermal patch manufacturing processes produce more waste (i.e., lower yield from theoretical) than other pharmaceutical processes.
Q5. Does CGMP regulations require three successful process validation batches before a new active pharmaceutical ingredient (API) or a finished drug product is released for distribution?
No. Neither the CGMP regulations nor FDA policy specifies a minimum number of batches to validate a manufacturing process. However, a minimum number of conformance (a.k.a. validation) batches necessary to validate the manufacturing processes is not specified. The manufacturer is expected to have a sound rationale for its choices in this regard.
Q6. FDA withdrew its draft guidance for industry on Powder Blends and Finished Dosage Units—Stratified In-Process Dosage Unit Sampling and Assessment. What were the Agency’s major concerns with this guidance?
FDA’s major concern was that sections V and VII of the withdrawn draft guidance no longer represented the Agency’s current thinking, as explained below.
Section V (Exhibit/Validation Batch Powder Mix Homogeneity) recommended that at least 3 replicate samples be taken from at least 10 locations in the powder blender, but that only 1 of the 3 replicates be evaluated to assess powder blend uniformity. The Agency currently recommends that all replicate samples taken from various locations in the blender be evaluated to perform a statistically valid analysis. This analysis can demonstrate that variability attributable to sample location is not significant and that the powder blend is homogenous. Statistical tools are available to ascertain both the number of replicates and the number of sampling locations across the blender that should be analyzed to conduct a valid analysis.
Section VII (Routine Manufacturing Batch Testing Methods) acceptance criteria designated to the Standard Criteria Method and the Marginal Criteria Method were based upon the limits published in the United States Pharmacopeia (USP) General Chapter <905> Uniformity of Dosage Units. However, the procedures and acceptance criteria in General Chapter <905> are not a statistical sampling plan and so the results of the procedures should not be extrapolated to larger populations. Therefore, because the procedure and acceptance criteria prescribed in section VII provided only limited statistical assurance that batches of drug products met appropriate specifications and statistical quality control criteria, FDA no longer supports their use for batch release. Currently, there are several standard statistical practices that, if used correctly, can help to ensure compliance with CGMP regulations, including 21 CFR 211.110, 21 CFR 211.160, and 21 CFR 211.165.
Q7. What are the Agency’s recommendations regarding in-process stratified sampling of finished dosage units?
Stratified sampling is recommended to be used when the population is known to have several subdivisions (i.e., locations), which may give different results for the quality characteristics measured. The Agency expects that no significant differences should exist between in-process locations that could affect finished product quality. Between- and within-location variability is a critical component of finished product quality and therefore should be evaluated. Please refer to ASTM E2709 and ASTM E2810 for further guidance on establishing acceptance criteria for a stratified sampling plan.
Q8. For drug products formulated with preservatives to inhibit microbial growth, is it necessary to test for preservatives as part of batch release and stability testing?
Yes. Two types of tests are generally used. Initially, firms perform antimicrobial preservative effectiveness testing to determine a minimally effective level of preservative. Once that level has been determined, firms may establish appropriate corresponding analytical test specifications. Firms may then apply the analytical tests for preservative content at batch release and throughout the shelf life of lots on stability.
Q9. Is it generally acceptable from a CGMP perspective for a manufacturer of sterile drug products produced by aseptic processing to rely solely on ISO 14644-1 and ISO 14644-2 when qualifying its facility?
No. It is generally not acceptable from a CGMP perspective for a manufacturer of sterile drug products produced by aseptic processing to rely solely on ISO 14644-1 and ISO 14644-2 when qualifying its facility. Rather, a manufacturer of sterile drug products produced by aseptic processing should use these ISO standards in combination with applicable FDA regulations, guidance, and other relevant references to ensure a pharmaceutical facility is under an appropriate state of control.
Q10. Are there any special processing or handling concerns for flexible intravenous (IV) solution bags?
Yes, due to their soft and flexible design, IV solution bags can be easily damaged if not handled properly during processing and labeling. A damaged IV solution bag may not protect the contents from exposure to microbiological contamination as intended. Detection of a damaged IV solution bag by leaks or by examination of the bag may not be possible. In fact, a microscopic defect may not be evident until microbiological contamination becomes visible, which is too late. Prevention of this potentially serious problem is important. FDA is aware of product recalls where IV products in flexible plastic bags were exposed to rough surfaces or sharp objects during labeling, creating microscopic punctures or weakening the bag surfaces.
Q11. What can IV drug manufacturers do to help prevent the loss of sterility due to compromised IV solution bag integrity during labeling?
The risk of loss of sterility during labeling can be reduced through the use of nonimpression printing devices for labeling. If a manufacturer uses labeling equipment to apply a label on an IV solution bag and that labeling equipment makes an impression on the IV bag, procedures should be in place to inspect the labeling equipment regularly, particularly after any maintenance is performed. Manufacturing equipment must not have any rough or sharp surfaces that will create punctures or areas of weakness in the IV solution bags.
Q12. Are there special manufacturing requirements for penicillin drugs?
Yes, all penicillin finished pharmaceutical manufacturers, including repackers, are required by the CGMP regulations to establish a comprehensive control strategy designed to prevent cross-contamination of other drugs with penicillin.
Q13. Many leading analytical balance manufacturers provide built-in “auto-calibration” features in their balances. Are such auto-calibration procedures acceptable instead of external performance checks? If not, then what should the schedule for calibration be?
The auto-calibration feature of a balance may not be relied upon to the exclusion of an external performance check (21 CFR 211.68). For a scale with a built-in auto-calibrator, we recommend that external performance checks be performed on a periodic basis, but less frequently as compared to a scale without this feature.
Q14. What are the cleaning validation requirements for potent compounds (e.g., compounds that are cytotoxic, mutagenic, or have high pharmacologic activity), and is dedicated equipment required?
Separation or dedication of equipment and facilities for the manufacture of potent compounds is not specifically required by CGMP regulations. However, manufacturers should identify drugs with such risks and define the controls necessary to eliminate risk of product cross-contamination in non-dedicated equipment and facilities. Such controls include proper cleaning, cleaning validation, and other contaminant controls.
Q15. Should laboratory glassware be included in a firm’s equipment cleaning validation program?
No. FDA does not expect laboratory glassware to be included in the processing equipment cleaning validation program. Glassware must, of course, be clean, and CGMP regulations consider laboratory equipment to be included within the scope of 21 CFR 211.67.
Q16. Can Total Organic Carbon (TOC) be an acceptable method for detecting residues of contaminants in evaluating cleaning effectiveness?
Yes. Since the publication of the inspection guide on cleaning validation in 1993, a number of studies have been published to demonstrate the adequacy of TOC in measuring contaminant residues.
17. Do firms need to quantify the total amount of residue remaining on equipment surfaces after manufacturing a product (before cleaning) to support cleaning validation studies?
No. In validating original cleaning procedures, firms need not quantify the level of chemical contamination remaining after manufacturing a product and before cleaning. Firms must, however, ensure that they validate proposed cleaning procedures as for routine use and should not pre-clean or otherwise attempt to make it easier for the procedures being validated to meet their cleaning objectives.
Q18. Must each batch of a United States Pharmacopeia (USP)-grade API be tested using the analytical procedures specified in the USP monograph?
No; however, each batch of a compendial article must conform to the monograph specifications/acceptance criteria. But the analytical procedures used to show conformance may differ from official USP methods if the alternative methods are fully validated, suitable for use, and give equivalent or better results than the official USP method.
Q19. 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 parts 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 was 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).
Q20. How does FDA interpret the regulations (21 CFR part 211) regarding the establishment of expiry dating for chemicals, reagents, solutions, and solvents?
If the purchased laboratory reagent or solution includes a manufacturer’s suggested use-by or expiry date, that date should be followed. For purchased laboratory reagents and solutions without a “use by” or expiry date, FDA would expect that an assessment be conducted (a literature review may be acceptable) of that specific chemical’s or chemical family’s stability and that an appropriate use-by or expiry date be determined.
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