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1. Do the CGMP regulations require a firm to retain the equipment status identification labels with the batch record or other file? Assuming each major piece of equipment has a unique cleaning and use log that is adequately retained, is it acceptable to discard these quick reference equipment labels?
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 ###; clean, ready for use as of d/m/y; and not clean. We see no value in the retention of such labels in addition to the required equipment log or batch record documentation. The labels serve a valuable, temporary purpose of positively identifying the current status of equipment and the material under process. Any status label should be correct, legible, readily visible, and associated with the correct piece of equipment. The information on the temporary status label should correspond with the information recorded in the equipment cleaning and use log, or the previous batch record for nondedicated equipment.
Labels are merely one way to display temporary status information about a piece of equipment. It is considered acceptable practice to display temporary equipment status information on dry-erase boards or chalkboards. And it would be appropriate for an FDA investigator to verify that the information on a temporary status label is consistent with the log.
References:
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 or closure or affect the integrity of the sample results. But whether the act of collecting a sample in the warehouse violates the CGMP 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 containers or 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 21 CFR 211.94 and 211.113(b)). This is to preserve the fitness for use of the remaining containers or closures as well as to 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 the original package). 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.
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3. 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?
A firm had multiple media fill failures. The media fill runs, simulating the filling process during production, were conducted inside an isolator. The firm used TSB (nonsterile 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 shapes 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, Eisenhuth, 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:
Date: 5/18/
4. 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. This should not of itself be a concern. The waste is usually due to the cumulative effect of roll splicing, line start-ups and stoppages, roll-stock changes, and perhaps higher rates of in-process sampling. This is most pronounced for processes involving lamination of rolls of various component layers. Roll-stock defects detected during adhesive coating of the roll, for example, can often only be rejected from the roll after final fabrication/lamination of the entire patch, which contributes to the final process waste stream.
We expect that validated and well-controlled processes will achieve fairly consistent waste amounts batch-to-batch. Waste in excess of the normal operating rates may need (see 21 CFR 21.192) to be evaluated to determine cause (e.g., due to increase in sampling or higher than normal component defects...or both) and the consequences on product quality assessed. We've seen a small number of cases where unusually high intra-batch rejects/losses were due to excessive component quality variability and poorly developed processes.
References:
21 CFR 211.100: Written procedures; deviations
21 CFR 211.103: Calculation of yield
21 CFR 211.110: Sampling and testing of in-process materials and drug products
21 CFR 211.192: Production record review
5. 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. The current FDA guidance on APIs (see guidance for industry ICH Q7 for APIs) also does not specify a specific number of batches for process validation.
FDA recognizes that validating a manufacturing process, or a change to a process, cannot be reduced to so simplistic a formula as the completion of three successful full-scale batches. The Agency acknowledges that the idea of three validation batches became prevalent in part because of language used in past Agency guidance. FDA's process validation guidance now recommends a product lifecycle approach. The emphasis for demonstrating validated processes is placed on the manufacturer&#;s process design and development studies in addition to its demonstration of reproducibility at scale, a goal that has always been expected.
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. The Agency encourages the use of science-based approaches to process validation.
In March , FDA revised the Compliance Policy Guide (CPG) Sec. 490.100 on Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to Pre-Market Approval. The CPG describes the concept that, after having identified and establishing control of all critical sources of variability, conformance batches are prepared to demonstrate that under normal conditions and operating parameters, the process results in the production of an acceptable product. Successful completion of the initial conformance batches would normally be expected before commercial distribution begins, but some possible exceptions are described in the CPG. For example, although the CPG does not specifically mention concurrent validation for an API in short supply, the Agency would consider the use of concurrent validation when it is necessary to address a true short-supply situation, and if the concurrent validation study conforms to the conditions identified in the CPG (see paragraph 4, a-c).
The conditions outlined in the CPG include expanded testing for each batch intended to address a short-supply situation. Expanded testing conducted according to an established validation protocol could provide added assurance that the batch meets all established and appropriate criteria before the API is used in the finished drug product. Additionally, confidence in the API manufacturing process may be gained by enhanced sampling (larger sample size representative of the batch) and perhaps the testing of additional attributes. Validated analytical methods are needed for testing every batch, including validation batches. The Agency would also expect the manufacturer to use a validation protocol that includes a review and final report after multiple batches are completed, even though the earlier batches may have been distributed or used in the finished drug product.
References:
6. Is it generally acceptable from a CGMP perspective for a manufacturer of sterile drug products produced by aseptic processing to rely solely on ISO -1 and ISO -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 [International Organization for Standardization] -1 Part 1: Classification of Air Cleanliness (-1) and ISO -2 Part 2: Specifications for Testing and Monitoring to Prove Compliance with ISO -1 (-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. Consequently, appropriate measures augmenting ISO&#;s recommendations (e.g., with microbiological data) would likely be expected for a firm to meet or exceed CGMP in a pharmaceutical facility.
Please understand that -1 and -2 have superseded Federal Standard 209E, Airborne Particulate Cleanliness Classes in Cleanrooms and Clean Zones (Federal Standard 209E). In November , the U.S. General Services Administration canceled Federal Standard 209E.
Although -1 and -2 are not FDA regulations or FDA guidance, the Agency believes that they are useful in facilitating the international harmonization of industrial air classification for nonviable particle cleanliness in multiple industries (e.g., computer, aerospace, pharmaceutical). As such, FDA adopted these particle cleanliness ratings in the guidance for industry Sterile Drug Products Produced by Aseptic Processing&#;Current Good Manufacturing Practice. However, due to the unique aspects of producing sterile drug products by aseptic processing (e.g., microbiological issues), an aseptic processing manufacturer should not rely solely on -1 and -2 when qualifying its facility.
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7. In , FDA issued a guidance entitled PAT - A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance that encouraged industry to modernize manufacturing through enhancements in process control. How can I implement PAT (process analytical technology)?
The objective of FDA's PAT program is to facilitate adoption of PAT. In our guidance, we discuss FDA's collaborative approach to promote industry uptake of new and beneficial technologies that modernize manufacturing operations and enhance process control. FDA recognizes that firms should be encouraged to promptly implement new systems that improve assurance of quality and process efficiency. Accordingly, our approach to PAT implementation is risk based and includes multiple options:
(1) PAT can be implemented under the facility's own quality system. CGMP inspections by a PAT-certified investigator can precede or follow PAT implementation.
(2) As another quality system implementation option, FDA invites manufacturers to request a preoperational review of their PAT manufacturing facility and process (see ORA Field Management Directive No.135).
(3) A supplement (Changes Being Effected (CBE), CBE-30, or Prior Approval Supplement (PAS)) can be submitted to the Agency prior to implementation, and, if necessary, an inspection can be performed by a PAT-certified investigator before implementation. This option should be used, for example, when an end product testing specification established in the application will be changed.
(4) A comparability protocol can be submitted to the Agency outlining PAT research, validation and implementation strategies, and time lines. Following collaborative review of the general strategy outlined in the comparability protocol, the regulatory pathway can include implementation under the facility's own quality system, a preoperational review, CGMP inspections (either before or after PAT implementation), a combination of these, or another flexible approach.
Manufacturers should evaluate and discuss with the Agency the most appropriate option for PAT implementation (see questions 8 and 9, below).
References:
8. How do I contact CDER with questions about PAT?
Manufacturers should contact the Office of Pharmaceutical Quality and/or the appropriate review division in CDER to discuss applicability of PAT to CDER-regulated products.
Contact for further information:
CDER Key Officials
Date Revised: 6/18/
9. How do I contact CBER with questions about PAT?
Manufacturers should contact the appropriate review division in CBER to discuss applicability of PAT to CBER-regulated products.
Contact for further information:
CBER Key Staff Directory
Date Revised: 9/16/
10. What is the acceptable media fill frequency in relation to the number of shifts? Normally, media fills should be repeated twice per shift per line per year. Is the same frequency expected of a process conducted in an isolator?
A firm's justification for the frequency of media fills in relation to shifts should be risk based, depending on the type of operations and the media fill study design. For closed, highly automated systems run on multiple shifts, a firm with a rigorous media fill design may be justified to conduct a lower number of total media fill runs. Such a program can be appropriate provided that it still ensures performance of media fills for each aseptic processing line at least semiannually. The guidance for industry on Sterile Drug Products Produced by Aseptic Processing states that "[A]ctivities and interventions representative of each shift, and shift changeover, should be incorporated into the design of the semi-annual qualification program." In addition, the EU Annex 1, Manufacture of Sterile Medicinal Products, states that "Normally, process simulation tests should be repeated twice a year per shift and process."
Certain modern manufacturing designs (isolators and closed vial filling) afford isolation of the aseptic process from microbiological contamination risks (e.g., operators and surrounding room environment) throughout processing. For such closed systems,1 if the design of the processing equipment is robust and the extent of manual manipulation in the manufacturing process is minimized, a firm can consider this information in determining its media fill validation approach. For example, it is expected that a conventional aseptic processing line that operates on two shifts be evaluated twice per year per shift and culminate in four media fills. However, for aseptic filling conducted in an isolator over two shifts, it may be justified to perform fewer than four media fill runs per year, while still evaluating the line semiannually to ensure a continued state of aseptic process control. This lower total number of media fill runs would be based on sound risk rationale and would be subject to reevaluation if contamination issues (e.g., product nonsterility, media fill failure, any problematic environmental trends) occur.
l This does not apply to RABS (restricted access barrier systems).
References:
Date: 12/3/
11. Why is FDA concerned about human topical antiseptic drug products?
FDA has identified several incidents of objectionable microbial contamination of topical antiseptic drug products (e.g., alcohol pads or swabs used to prepare the skin prior to an injection). Microbial contamination may be caused by substandard manufacturing practices, and the Agency is concerned about safety risks, such as from infection, associated with this contamination.
Date: 12/21/
12. What specific CGMP regulations might be useful to manufacturers of topical antiseptic drug products?
Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act requires all drugs to be manufactured in conformance with CGMP. The CGMP regulations in 21 CFR parts 210 and 211 for finished pharmaceuticals apply equally to over-the-counter (OTC) and prescription (Rx) drug products (see Compliance Policy Guide Sec. 450.100).
The CGMP regulations provide the minimum legal requirements for conducting reliable operations (see 21 CFR part 211). Some relevant CGMP regulations, with a brief description, are given below:
Manufacturing Design and Control: CGMP Requirements and Recommended Guidance for Manufacturers
Design manufacturing facilities
(§ 211.42) and processes (see below) to prevent microbial contamination:
For nonsterile drug products,
establish control procedures to monitor output and validate processes to include bioburden testing (§§ 211.110(a)(6)), 211.111) and establish and follow written procedures designed to prevent the introduction of objectionable microorganisms (§ 211.113(a)).
For sterile drug products,
establish and follow written procedures designed to prevent microbial contamination (§ 211.113(b)). See the guidance for industry Sterile Drug Products Produced by Aseptic Processing&#;Current Good Manufacturing Practice.
(§ 211.110(a))
.Implement and validate needed changes when deficient manufacturing steps, equipment, or raw materials may be adversely affecting process control.
See the guidance for industry Process Validation: General Principles and Practices.
Ensure that operating procedures
will consistently produce a quality product (§ 211.100).
Review and evaluate any deviations or discrepancies documented during manufacturing and testing to determine if a product lacks assurance of sterility (for sterile antiseptics) or may be contaminated with
objectionable microorganisms
(for nonsterile antiseptics).
Document and implement any corrective actions deriving from the evaluation (§ 211.192).
Ensure that all equipment,
including water systems, operates consistently and is clean, sanitary, and suitable for its intended use (§§ 211.63, 211.65, 211.67, and 211.68).
Establish and follow in-process bioburden testing
procedures to help monitor in-process control, including understanding the bioburden challenge to a final sterilization process (§ 211.110(a)(6)).
Components, In-Process Materials, Containers or Closures, and Finished Product Testing: CGMP Requirements for Manufacturers
Establish appropriate written testing standards/specifications and sampling plans
for components, in-process materials, containers or closures, and finished products (§ 211.160).
Establish procedures for testing
and approval or rejection of components, drug product containers, and closures (§ 211.80).
Test
each lot of a drug product component and container or closure, including those that may be vulnerable to microbiological contamination (§211.84)(d)(4-5), including applicator material (e.g., cotton pads) and water used as an ingredient in the product
.before a batch disposition decision is made.
Test each batch of a sterile product for sterility (§
211.167)
.
Test each batch of a non-sterile product to ensure absence of objectionable microorganisms (§
211.165(b))
.
Management
The CGMP regulations require that the management of a manufacturing facility maintains a well-functioning quality system, which includes an effective quality unit vested with the responsibilities and authorities required under CGMP (§ 211.22). See ICH guidances for industry Q9 Quality Risk Management and Q10 Pharmaceutical Quality System.
References:
Date: 12/21/
13. How can manufacturers assess and address the risk of microbiological contamination of topical antiseptics?
Because there are potentially many different root causes of product contamination by microorganisms, it is imperative that manufacturers perform a manufacturing risk assessment to understand manufacturing failure modes and implement prevention measures.
In addition, any risk assessment approach should be informed by an understanding of the microbial contamination vulnerabilities of the concerned product. For example, some product considerations for manufacturers include, but are not limited to:
Determine the types of microbes that might survive or thrive in your products. Provide additional controls and testing based on the output of the risk assessment to ensure product quality.
Ensure that your microbial recovery methods are capable of detecting the types of microbes that may affect product quality.
Evaluate risk of contamination from components, including during component production, storage, or due to the intrinsic risk from source materials. Consider all possible sources of microbial contamination, including the following:
Components or products stored in open bins can be at risk for contamination by spore-forming microbes, such as Bacillus cereus, as well as by Serratia species and other worrisome airborne microbes (see the FDA news release and Morbidity and Mortality Weekly Report, referenced below). Manufacturing areas exposed to windy or poor HVAC conditions may increase the potential for this environmental contamination risk.
Some materials, especially from natural sources, may have high or objectionable intrinsic bioburden.
Water quality can pose a significant risk, as most antiseptics include water as a key ingredient.
Contaminated purified water has been the root cause of multiple recalls of antiseptics, including instances of antiseptics contaminated with Burkholderia (previously Pseudomonas
) cepacia
, an opportunistic pathogen.Unsanitary practices or sources.
When manufacturing in areas with high humidity, molds can be of special concern.
References:
Date: 12/21/
14. Can Leptospira species penetrate sterilizing-grade filters? If so, what should manufacturers keep in mind in their ongoing lifecycle risk management efforts to ensure microbial control?
FDA is aware of a report of Leptospira licerasiae contamination in cell cultures (see Chen, Bergenvin, et al. ). There is no indication that this bacterium ultimately contaminated either the finished drug substance or drug product. This bacterium has been found to pass through 0.1 µm pore size rated sterilizing-grade membrane filters. While this specific species was the identified contaminant in this case, other Leptospira species also are capable of passing through 0.1 µm pore size rated filters (see Faine ). Compendial microbiological test methods typically used in association with upstream biotechnology and pharmaceutical production are not capable of detecting this type of bacteria. Whether this apparently rare contamination risk may be more widespread is unknown, and we are sharing this information so that manufacturers can consider whether this hazard may be relevant to their operations.
Leptospira are Gram-negative aerobic spirochetes that are flexible, highly motile, and spiral-shaped with internal flagella. The bacteria measure 1μm in diameter and 10-20 μm in length. Leptospira are obligate aerobes that use oxygen as the electron receptor and long-chain fatty acids as a major source of energy. While some of the Leptospira are harmless fresh-water saprophytes, other species are pathogenic and can cause leptosporosis, a significant disease in humans and animals (Ricaldi, Fouts, et al. ; Matthias, Ricaldi, et al. ; Bharti, Nally, et al. ). Based on current information, Leptospira contamination does not appear to occur frequently, and purification steps that follow cell culture in a typical biotechnology operation would be expected to prevent carryover to the finished drug substance. Testing of bulk drug substances produced in the reported cases did not detect the Leptospira species, and no evidence of deleterious effects on in-process product were observed in the known case study. However, we are providing this communication to alert manufacturers that these types of bacteria can potentially:
As a general principle, manufacturers should use sound risk management and be aware of unusual microbiota reported in the literature that may impact their manufacturing processes (e.g., cell culture biotechnology, conventional sterile drug manufacturing). Manufacturers should assess their operations, be aware of potential risks, and apply appropriate risk management based on an understanding of possible or emerging contamination risks (see section 18.3 in ICH guidance for industry Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients). As appropriate, preventive measures should be implemented during the product and process lifecycle. To illustrate, if leptospiral contamination is considered possible, or has occurred, risk mitigation procedures and practices for this microorganism should include at least the following:
(1) Review of available published articles from the scientific literature and technical reports by related industry organizations that may provide further understanding on how to mitigate this contamination hazard.
(2) Use of molecular or nonconventional microbial monitoring methods at appropriate intervals to detect microbial flora that may exist in processing steps or in the immediate environment, but are not readily detected by current routine methods. Such expanded testing should be used to modify the strategy (e.g., timing, frequency, types of tests) of detection and control in the event of newly identified risk posed by the viable, but not easily cultured, microorganism.
Examples include: a. Use of specialized media such as Ellinghausen McCullough Johnson Harris (EMJH) medium (Ellinghausen and McCullough ) or other suitable media (Rule and Alexander ). It should be noted that these bacteria typically grow very slowly. b. Use of validated polymerase chain reaction (PCR) methods (e.g., as an investigative tool) for rapid screening and detection of spirochete bacteria. c. Consideration of special stain techniques or other means to identify the presence of Leptospira (Frank and Kohn ).
(3) Use of conventional approaches. Firms should continue to properly employ basic, standard microbiology laboratory practices to detect contamination. For example, the laboratory should ensure that microscopic examination is part of its routine cell culture process control program, as it provides an important means of detecting microbial contaminants that may not readily grow on conventional media.
(4) Implementing such quality risk-management measures into the initial design (i.e., preventive actions) and promptly implementing an appropriate corrective action plan in response to newly identified contamination sources, throughout the life cycle of the product.
References:
Link to hait
Date: 12/20/
15. 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.
References:
Date: 8/6/
16. Why is FDA concerned about proper sampling of powder blends?
The CGMPs require that all sampling plans be scientifically sound and representative of the batch under test (see 21 CFR 211.160(b)). Further, in-process testing of powder blends to demonstrate adequacy of mixing is a CGMP requirement (21 CFR 211.110). Between- and within-location variability in the powder blend is a critical component of finished product quality and therefore should be evaluated. Drug product manufacturers need to use a science- and risk-based sampling approach to ensure (a) adequacy of blend mixing and (b) that sampling of the blend is done at a suitable juncture in the manufacturing process. The sampling and analysis needs to ensure that no differences exist between locations in a blend that could adversely affect finished product quality. Traditional sampling using a powder-thief may have drawbacks and limitations, such as causing disturbance to the powder bed, powder segregation, or other sampling errors. However, powder-thief sampling remains widely used and provides reliable results in many cases. The Agency encourages firms to adopt more innovative approaches to ensuring adequacy of mixing (see, e.g., the guidance for industry PAT&#;A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance). If a manufacturer proposes to use a thief sampling method, the reliability of the method should be evaluated as part of analytical methods development.
References:
Date: 8/6/
17. What are some recommended innovative approaches to ensuring adequacy of mixing of powder blends?
Innovative approaches to consider include, but are not limited to: (a) PAT real-time monitoring and feed-forward controlling of the powder blending process (see the guidance for industry PAT&#;A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance) and (b) use of statistical process control tools to monitor the powder blending process and to maintain a state of control. When a manufacturer decides to implement PAT or other process-monitoring and control techniques for powder blend homogeneity assessment, its decision should be supported with appropriate data and rationale using a science- and risk-based approach. For example, the effective sample size of powder examined by PAT probes has to be estimated such that the scale of scrutiny of the PAT powder blending monitoring can be justified (Wu, Tawakkul, et al. ). The number of PAT probes and their locations also have to be justified. If a scientifically sound PAT monitoring and control strategy is established, it can facilitate the assessment of (a) variability across locations within the powder bed (El-Hagrasy, Morris, et al. ), (b) variability over time of one location, and (c) potential correlation between the powder sample and the unit dosage form.
References:
Date: 8/6/
18. 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 E and ASTM E for further guidance on establishing acceptance criteria for a stratified sampling plan. References:
Date: 8/6/
19. For a nonsterile compendial drug product that includes an antimicrobial preservative in its formulation, may I release and market lots of this drug product with initial out-of-specification total aerobic plate counts if these lots test within specification 2 weeks later?
No. 21 CFR 211.113(a) requires appropriate written procedures to be established and followed during manufacturing to prevent objectionable microorganisms in drug products not required to be sterile. Additionally, the second paragraph of USP General Chapter <51> Antimicrobial Effectiveness Testing reads: Antimicrobial preservatives should not be used as a substitute for good manufacturing practices, solely to reduce the viable microbial population of a nonsterile product, or control the presterilization bioburden of a multidose formulation during manufacturing. Drug manufacturers should not rely on antimicrobial preservatives to reduce initial out-of-specification plate counts to within-specification levels and then market the product. Section 211.165(f) mandates that drug products failing to meet established standards or specifications be rejected. The initial test results exhibiting out-of specification levels of microbes are not disqualified even if subsequent test results are within specifications. In such cases, FDA still expects the manufacturer to reject the drug product based on the initial results. It is also not acceptable for manufacturers to allow an inappropriately long time (e.g., weeks) to pass before testing the product, which might permit the preservative to reduce levels of microbes possibly introduced during manufacture and thus avoid out-of-specification test results. Finally, drug manufacturers should review their manufacturing process to determine procedures or equipment that might introduce contaminating microorganisms into the process or product.
References:
Date: 6/11/
20. Do pharmaceutical manufacturers need to have written procedures for preventing growth of objectionable microorganisms in drug products not required to be sterile? What does objectionable mean anyway?
Yes, CGMP regulations do require these written procedures. 21 CFR 211.113(a) specifies that appropriate written procedures be established and followed to prevent growth of objectionable microorganisms in drug products not required to be sterile. Even though a drug product is not sterile, a firm must follow written procedures that proactively prevent introduction and proliferation of objectionable microorganisms. 21 CFR 211.165(b) states that &#;[t]here shall be appropriate laboratory testing, as necessary, of each batch of drug product required to be free of objectionable microorganisms&#; before it is released for distribution. The meaning of the term objectionable needs to be evaluated on a case-by-case basis by each drug manufacturer. The primary meaning relates to microbial contaminants that, based on microbial species, numbers of organisms, dosage form, intended use, patient population, and route of administration, would adversely affect product safety. Microorganisms may be objectionable for several reasons; for example, they:
Establishing production time limits is an example of a control to prevent growth of objectionable microorganisms. Per 21 CFR 211.111, time limits for the completion of each phase of production, when appropriate, must be established and followed. For example, if a firm finds it necessary to hold a bulk topical or liquid product for several months until it is filled, the firm might establish a holding time limit to help prevent objectionable microbial buildup. Validation and control over microbial content of purified water systems used in certain topical products are also examples of such procedures (see FDA guidance, referenced below).
References:
Date: 6/11/
21. 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.
References:
Date: 6/11/
22. Is parametric release an appropriate control strategy for sterile drug products that are not terminally sterilized?
No. Parametric release is only appropriate for terminally sterilized drug products. Although both terminally sterilized and aseptically processed drug product batches are required to meet the sterility test requirement (see 21 CFR 211.167(a)) before release to the market, there are inherent differences between the production of sterile drug products using terminal sterilization and aseptic processing.
Products that are terminally sterilized are rendered sterile in their final, sealed units by sterilizers. Discrete physical parameters (e.g., temperature, pressure, and time) are continuously measured and controlled with robust precision and accuracy during processing. Additionally, parametric release incorporates a sterilization load monitor that is integral to satisfying the requirement for a sterility test (see § 211.167(a)) by confirming that the load has been exposed to the prescribed physical conditions. This allows manufacturers to couple adherence to sterilization cycle parameters with a load monitor to determine thermal lethality, thereby directly confirming sterility and substituting for the sterility test.
In contrast, aseptic processes do not subject the final, sealed drug product to a sterilization cycle, and monitoring the sterility hazards to drugs manufactured throughout aseptic manufacturing operations relies on indirect measurements. Sterilization processes (e.g., filtration) for the drug occur before further manipulations that are performed in Class 100 (ISO 5) environments where transient events can present microbial contamination risks during the manufacturing process. Consequently, indirect measurements used in aseptic processing provide limited information to conclude whether a batch is sterile. Even contemporary aseptic operations conducted in closed RABS and isolators can experience sterility and media fill failures, despite the substantial robustness of these technologies over traditional cleanroom and open RABS operations. The sterility test is therefore an essential element to monitor the state of control of an aseptic operation, and it is the last step in a series of fundamental, required controls that collectively contribute to the minimum assurance that a given manufacturing operation produced a drug that meets its sterility claim. The sterility test also protects patients by potentially preventing the distribution of an aseptically processed drug product batch posing serious safety concerns that would not otherwise be readily detected.
All quality control tests, including the sterility test, have limitations. Although the sterility test may not exhaustively assess batch sterility, the sterility test is, nonetheless, a critical component of a comprehensive control strategy that is designed to prevent microbiological contamination of drug products purporting to be sterile (21 CFR 211.113(b)). Innovations in sterility testing (e.g., rapid microbiological methods, genotyping) and the integration of these innovations into manufacturing operations may further improve prompt operational feedback, which can result in significant batch release efficiencies while ensuring equivalent or better ability to detect nonsterility compared with the compendial method. FDA encourages the use of beneficial testing innovations in conjunction with advanced manufacturing technologies (e.g., robotic isolators) to enhance process design and improve both microbial detection and identification.
Date: 8/11/
23. Does FDA consider ophthalmic drug products1 to be adulterated when they are not manufactured under conditions that ensure sterility throughout their shelf life and, in the case of multidose products, that prevent harmful microbial contamination throughout their in-use period?
Product sterility is a critical quality attribute (CQA) for ophthalmic drug products.2 Recent cases of microbially contaminated ophthalmic drug products leading to serious injury and death, as well as recent recalls, highlight the importance of product sterility.3 Manufacturers of drug products, including sterile products offered or intended for ophthalmic use, must comply with CGMP requirements in 21 CFR parts 210 and 211. Failure to comply with these requirements will cause affected products to be deemed adulterated under section 501(a)(2)(B) of the FD&C Act.
Sterile drug products must meet specific CGMP requirements for personnel, buildings and facilities, materials, production and controls, and testing, as appropriate, to ensure product sterility at the time of manufacture and throughout the product&#;s shelf life. FDA has published guidance4 to provide clarity on how manufacturers can meet CGMP requirements in 21 CFR parts 210 and 211 when manufacturing sterile drug and biological ophthalmic products using aseptic processing. Some of the relevant regulations and guidance applicable to products for ophthalmic use are summarized below.
FDA assesses compliance with these and other applicable CGMP requirements through facility inspections under section 704(a)(1) of the FD&C Act, records requests under section 704(a)(4) of the FD&C Act, and other oversight tools. Manufacturers can find additional insight in the guidance for industry Submission Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products, which, although focused on application submission, includes information about the efficacy of sterilization processes.
1 As defined in guidance for industry Quality Considerations for Topical Ophthalmic Drug Products (December ).
2 See 21 CFR 200.50(a)(1).
3 See FDA&#;s alerts and warnings about eye drops at https://www.fda.gov/drugs/buying-using-medicine-safely/what-you-should-know-about-eye-drops.
4 See FDA&#;s guidance for industry Sterile Drug Products Produced by Aseptic Processing&#;Current Good Manufacturing Practice.
5 This is consistent with USP General Chapter <771> Ophthalmic Products&#;Quality Tests.
6 Liquid ophthalmic products in multidose containers should contain one or more suitable and harmless substances that will inhibit the growth of microorganisms; see 21 CFR 200.50(b). See also USP General Chapter <51> Antimicrobial Effectiveness Testing.
7 USP General Chapter <51> Antimicrobial Effectiveness Testing.
References:
Date: 5/22/
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Contains Nonbinding Recommendations
1. 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. The frequency of performance checks depends on the frequency of use of the scale and the criticality and tolerance of the process or analytical step. Note that all batches of a product manufactured between two successive verifications would be affected should the check of the auto-calibrator reveal a problem. Additionally, the calibration of an auto-calibrator should be periodically verified&#;a common frequency is once a year&#;using National Institute of Standards and Technology (NIST)-traceable standards or NIST-accredited standards in use in other countries.
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2. Do CGMPs require that forced degradation studies always be conducted of the drug product when determining if a drug product stability test method is stability indicating?
No. Drug product stress testing (forced degradation) may not be necessary when the routes of degradation and the suitability of the analytical procedures can be determined through use of the following:
Additional supportive information on the specificity of the analytical methods and on degradation pathways of the drug substance may be available from literature sources. Section 211.165(e) of the CGMP regulations states that the accuracy, sensitivity, specificity, and reproducibility of test methods shall be established and documented (21 CFR 211.165(e)). Further, 21 CFR 211.166(a)(3) requires that stability test methods be reliable, meaningful, and specific, which means that the content of the active ingredient, degradation products, and other components of interest in a drug product can be accurately measured without interference, often called stability indicating. The CGMP regulations do not specify what techniques or tests are to be used to ensure that one&#;s test methods are stability indicating. However, evaluating the specificity of the test methods during forced degradation studies (i.e., exposing the drug to extremes of pH, temperature, oxygen, etc.) of the drug substance and drug product often is necessary to ensure that stability test methods are stability indicating. But in certain circumstances, conducting a forced degradation study of just the drug substance may be sufficient to evaluate the stability-indicating properties of a test method. Generally, in determining whether it is necessary to conduct forced degradation studies of the drug product, the specificity of the test method should be evaluated for its ability to assay drug substance, degradants, and impurities, in the presence of each other, without interference. The evaluation also should provide assurance that there is not a potential for interaction between the drug substance, degradants, impurities, excipients, and container-closure system during the course of the shelf life of the finished drug product. Last, the rationale for any decision made concerning the extent of the forced degradation studies conducted as well as the rationale for concluding that a test method is stability indicating should be fully documented.
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3. When performing the USP General Chapter <788> Particulate Matter in Injections test for a large volume parenteral (LVP), is it acceptable to take the average among the units tested to determine if the batch meets its specification for this attribute?
No. It is not acceptable to take the average among the LVP units tested in each batch/lot when following this method because the purpose of this method is to measure and limit intra-batch variability.
Particulate matter refers to small, subvisible particles. General Chapter <788> provides two tests for detecting such particulates&#;light obscuration and microscopic assay. Both are generally accepted for use in testing LVPs and small volume parenterals (SVP) for the determination of subvisible particulate matter. Normally, samples are first tested by the light obscuration method; if the sample fails the specified limits, the microscopic assay method can then be used. However, the microscopic method can be the sole test if there is a documented technical reason or interference from the product under test that would make the light obscuration method unsuitable or the results invalid.
Confusion about when averaging data is and is not acceptable is probably due to the sample preparation method for the light obscuration test (General Chapter <788>). At least 2, 5-mL aliquots from each sampled unit or the pooled sample (see below) are to be used in the particulate count determination, and the results from these aliquots are to be averaged for comparison with the specification. Note that the average is of the results from examining each aliquot and not between units. (The results of the first aliquot examined by light obscuration are to be discarded, and the subsequent aliquots&#;2 or more&#;are retained.) Pooling units prior to analysis is permitted only if the volume in each unit is less than 25 mL, in which case 10 or more units may be pooled. If the volume in the SVP or LVP is 25 mL or more per unit, single units are to be examined by this method (General Chapter <788>).
Results among the test units cannot be averaged because particulate matter is assumed to be non-uniformly dispersed throughout the lot. The intent of assessing results from each individual unit is to ensure adequate representation of the lot and to detect potential variation within a lot.
As to the number of individual units to be tested for LVP and SVP units having a volume of 25mL or more, the USP states that the number of units tested depends on "statistically sound sampling plans," and "sampling plans should be based on consideration of product volume, numbers of particles historically found to be present in comparison to limits, particle size distribution of particles present, and variability of particle counts between units." The USP also suggests that the total number of units tested for any given batch may be less than 10 units (for LVP and pooled SVPs) with proper justification. This is consistent with the CGMP requirement for statistical sampling plans (see 21 CFR 211.165).
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4. 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 , a number of studies have been published to demonstrate the adequacy of TOC in measuring contaminant residues.
We think TOC or TC can be an acceptable method for monitoring residues routinely and for cleaning validation. But in order for TOC to be functionally suitable, it should first be established that a substantial amount of the contaminating material(s) is organic and contains carbon that can be oxidized under TOC test conditions. This is not a trivial exercise because we know that some organic compounds cannot be reliably detected using TOC.
TOC use may be justified for direct surface sample testing as well as indirect (rinse water) sample testing. In either case, because TOC does not identify or distinguish among different compounds containing oxidizable carbon, any detected carbon is to be attributed to the target compound(s) for comparing with the established limit. Thus, a firm should limit background carbon (i.e., carbon from sources other than the contaminant being removed) as much as possible. The established limit, or the amount of residue detected for comparison to the specification, should correct for the target material's composition of carbon. As for any cleaning method, recovery studies are necessary (21 CFR 211.160(b)). If TOC samples are being held for long periods of time before analysis, a firm should verify the impact of sample holding time on accuracy and limit of quantitation.
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5. Would a paramagnetic or laser oxygen analyzer be able to detect all possible contaminants or impurities in a medical gas?
No. Although paramagnetic and laser oxygen analyzers are very accurate and reliable when calibrated correctly, these types of analyzers can only detect the presence and measure the strength of oxygen. They are unable to detect contaminants or impurities that may be present, such as hydrocarbons or arsenic compounds. The USP monograph test for oxygen does not include an impurity screen, and other analyzers may need to be used. For example, assays for hydrocarbon impurities are routinely conducted during the oxygen manufacturing process even though the USP does not list hydrocarbons as an impurity. Also, alternative methods may be needed to test high-pressure cylinders for cleaning solution residues.
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6. Can up to 12-month expiration dating be assigned to oral solid and liquid dosage forms repackaged into unit-dose containers based on guidance in the May draft revision of Compliance Policy Guide Sec. 480.200 Expiration Dating of Unit Dose Repackaged Drugs (CPG b.11)?
No. In May , a Notice of Availability of the draft revision of FDA&#;s Compliance Policy Guide Sec. 480.200 Expiration Dating of Unit-Dose Repackaged Drugs (CPG b.11) was announced in the Federal Register. The draft CPG specifies certain conditions when it may be possible to assign up to 12-month expiration dating to nonsterile solid and liquid oral drug products repackaged into unit-dose containers without conducting new stability studies to support the length of expiration dating on the repackaged products. The draft CPG was prompted by USP standards for assigning up to a 12-month beyond-use date to nonsterile solid and liquid oral dosage forms dispensed in unit-dose containers. (Beyond-use date is USP&#;s pharmacy dispensing term for specifying a date on a prescription container beyond which a patient should not use the product.) If finalized, FDA&#;s draft CPG would replace the current version of CPG Sec. 480.200. The current version of CPG Sec. 480.200 was finalized in March and provides conditions under which FDA will not initiate action for assigning up to 6-month expiration dating for drug products repackaged into unit-dose containers without conducting new stability studies.
FDA is conducting a stability study of certain commercially repackaged drugs to determine the suitability of the draft revision of CPG Sec. 480.200. Until the stability study is complete and FDA evaluates all comments submitted to the public docket in response to the May Federal Register Notice of Availability, the Agency does not intend to make a final decision on the draft revision of CPG Sec. 480.200. Consequently, at this time and until FDA announces a final decision on the draft CPG, the current CPG Sec. 480.200, which was finalized in March , is in effect.
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7. Is it ever appropriate to use an unvalidated method to test a drug component or product?
The CGMP regulations require the use of validated methods when performing routine testing of raw material, in-process material, and finished products (21 CFR 211.160, 211.165(e), and 211.194) for manufacturing finished drug products. Method validation studies establish proof that a method is suitable for its intended purpose. The purpose is generally to measure a particular material&#;s conformance to an established specification (see the ICH guidance for industry Q2 (R1) Validation of Analytical Procedures: Text and Methodology). FDA recognizes, however, that test methods developed based on scientifically sound principles (e.g., sufficient accuracy and precision) but that are not fully validated may be suitable for use in certain instances during an investigation of a potential quality problem or defect. For example, investigation of an atypical impurity or possible contaminant of a drug product or any of its components (e.g., oversulfated chondroitin sulfate in heparin) may indicate the need for additional methods beyond routine quality control tests. Such testing may be critical to promptly and adequately evaluate the problem and protect public health. Full evaluation of a method&#;s robustness and reproducibility may not initially be feasible or appropriate when conducting tests in certain investigations. When a company, for whatever reason, tests drug components or products using an unvalidated method, it is important to recognize the possibility of greater uncertainty in the test results derived from these unvalidated test methods, as compared to validated test methods. Nevertheless, the resulting data may yield important information indicating the need for prompt corrective action. Accordingly, we expect all such test results on drug components or products to be reviewed to assess the need for follow-up action (21 CFR 211.192 and 211.180(e)). References:
Date: 1/6/
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8. Did FDA withdraw the Guideline on Validation of the Limulus Amebocyte Lysate Test as an End-Product Endotoxin Test for Human and Animal Parenteral Drugs, Biological Products, and Medical Devices?
Yes, FDA withdrew the Guideline. The Guideline is considered obsolete and does not reflect the Agency&#;s current thinking on the topic. Date: 7/12/
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9. Where can drug manufacturers find information regarding endotoxin testing?
USP publishes endotoxin testing recommendations and acceptance criteria in USP General Chapter <85> Bacterial Endotoxins Test. General Chapter <85> provides methods and calculation of limits for drugs. FDA may, as needed, provide additional guidance to clarify the Agency&#;s current thinking on use of Limulus Amebocyte Lysate (LAL), recombinant LAL, and other endotoxin testing methods.
References:
Date 7/12/
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10. Is it acceptable to release non-penicillin finished drug products to market if the products may have been exposed to penicillin, as long as the non-penicillin products are tested and no penicillin residue is found?
21 CFR 211.176, Penicillin Contamination, allows marketing of non-penicillin finished drug products if they are tested using the codified method and found not to be contaminated with penicillin. However, it is not acceptable to release the product unless all other applicable CGMP requirements have been met. In some cases, firms inappropriately apply § 211.176 to market products that have not been produced under CGMP. Notably, 21 CFR 211.42(d) requires that manufacturing operations for penicillin drug products be performed in facilities separate from those used for non-penicillin human drug products. Similarly, 21 CFR 211.46(d) requires that air-handling systems for penicillin and non-penicillin drug products be completely separate. For example, if a non-penicillin product is made in a facility that shares equipment or an air-handling system with a penicillin production area (in violation of § 211.46(d)), the non-penicillin product cannot be made CGMP-compliant through testing alone. However, if a door is accidentally left open between a penicillin-dedicated area and other separate production areas, resulting in possible exposure of the other areas to penicillin, testing those other products for penicillin could justify their release for distribution. However, as per 21 CFR 211.165, all sampling plans and acceptance criteria used for testing and release of the non-penicillin product, including any testing for penicillin contamination, must be adequate to ensure the tested product meets all of its specifications.
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Date: 6/17/
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11. Can a facility that produced penicillin dosage forms be decontaminated and renovated for production of non-penicillin dosage forms, provided there is no further penicillin production in the renovated facility? Yes; however, decontamination can be extremely difficult. The decontamination process must include scientifically sound studies demonstrating the efficacy of the decontamination agents, extensive and statistically appropriate sampling throughout the areas before and after decontamination to verify cleanliness, and appropriate testing of such samples with a validated analytical method having an appropriate limit of detection. The CGMP regulations in 21 CFR 211.176 require that if a reasonable possibility exists that a non-penicillin drug product has been exposed to cross-contamination with penicillin, the non-penicillin product must be tested for the presence of penicillin and cannot be marketed if detectable levels are found using the codified method. Such a reasonable possibility may be present if decontamination has not been conducted effectively. Although CGMP regulations do not prohibit decontamination and conversion, the difficulty of cleaning up penicillin residues can make the process daunting (see also FDA Guide to Inspections, referenced below).
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Date: 6/17/
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12. Is there an acceptable level of penicillin residue in non-penicillin drug products? No. There is no established safe level of penicillin residue in non-penicillin drug products (see FDA guidance for industry, referenced below). The CGMP regulations in 21 CFR 211.42(d) and 211.46(d) require that penicillin-manufacturing facilities and air-handling systems must be adequately separated from those used to manufacture other drugs. 21 CFR 211.176 states that a non-penicillin drug product must not be marketed if penicillin is found when tested according to the codified procedure. Alternative validated test methods to detect penicillin residues may be used if demonstrated to be equivalent to or better than the referenced method.
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Date: 6/17/
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13. For injectable drugs in multiple-dose containers, is the number of entries to withdraw a dose a factor in determining the expiration date? Generally, no. Unless the multiple-dose container is labeled to yield a specific number of doses of a stated volume, there is no limit to the number of withdrawals that may be made from a multiple-dose container before the drug is depleted or reaches its expiration date. The primary concern with multiple-dose containers is the potential for contaminating the product during multiple penetrations through the container stopper. Although the expiration date assigned to such products would be based on the stability of the drug product, stability protocols should include requirements for testing and evaluating container-closure integrity. Container-closure integrity testing may include physically testing the closure seal by using a leak test and monitoring the system&#;s ability to prevent microbial contamination. For multiple-dose injection product containers, functionality testing can include a self-sealing capacity test involving multiple penetrations of a hypodermic needle through the container stopper (see USP references below). Furthermore, injectable drug products in multiple-dose containers are generally formulated with an antimicrobial agent or preservative&#;or they contain inherently antimicrobial ingredients&#;and must meet requirements in accordance with the approved application (new drug application/abbreviated new drug application, biologics license application) and/or USP requirements.
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Date: 6/17/
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14. How long may a firm store in-process/intermediate powder blends and triturations, sustained-release pellets/beads, and tablet cores, absent separate stability studies, before using them in finished drug products? For in-process/intermediate materials that are chemically and physically stable, a risk- and science-based assessment process can help identify which material attributes and process parameters might affect the critical quality attributes of the finished drug product in which they are to be used. This assessment should be designed to ensure that materials held (under appropriate storage conditions) for a specified period are appropriate for use in manufacturing the finished drug product without having to conduct formal stability studies to verify the holding periods. In some instances, the risk assessment may include sampling and testing the material being held (at the stage determined by the risk assessment) to verify the manufacturing holding period. However, for unstable materials or for materials held longer than the period established in the risk assessment, firms should conduct stability studies according to an approved stability protocol to verify holding periods. The stability studies should include evaluations of the in-process/intermediate materials up to the time of their use in manufacturing a finished drug product and should include long-term monitoring of finished product batches manufactured with the in-process/intermediate materials. In the latter case, until appropriate stability data are generated, firms should calculate the expiration date assigned to finished product batches based on the date of manufacture/release of the in-process/intermediate material rather than on that of the finished product.
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Date: 6/17/ Back to Top
15. What material can be used as instrument calibration standards for chromatographic systems? For chromatographic systems, instrument calibration standards should be chosen from highly purified materials that are well characterized and can be accurately weighed. Standards can be compendial (from USP) or non-compendial (e.g., from NIST, a chemical supplier, or produced in-house). Substances obtained from a chemical supplier or produced in-house should be purified and characterized using validated purification processes and validated characterization methods. Purification is necessary because impurities can add variation and interfere with analytical methods. Finished dosage forms generally should be avoided as standards because excipients in the finished dosage form may interfere with analysis.
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Date: 8/12/ Back to Top
16. What material can be used for system suitability? FDA expects system suitability to be checked using qualified primary or secondary reference standards and any materials necessary to ensure adequate method performance. A new batch of highly pure reference standard material (e.g., from a chemical supplier or produced in-house) should be qualified against the primary reference standard. Finished dosage forms or APIs that have not been qualified as reference standards should not be used for system suitability testing. Even when API or a finished dosage form has been properly qualified as a reference standard, it should not be used for system suitability testing if it is from the same batch as sample(s) being tested. Written procedures must be established and followed (21 CFR 211.160 and 211.194). All data &#; including obvious errors and failing, passing, and suspect data &#; must be in the CGMP records and subject to review and oversight. Records must be complete (e.g., 21 CFR 211.68(b), 211.188, and 211.194) and subjected to adequate review (21 CFR 211.68(b), 211.186(a), 211.192, and 211.194(a)(8)).
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Date: 8/12/ Back to Top
17. Is it ever appropriate to perform a &#;trial injection&#; of samples? No. FDA has observed at some drug manufacturers the practice of a trial injection where a sample of a lot is injected into the chromatographic system with the intention of obtaining an unofficial result (e.g., passing or failing). This is in contrast to the appropriate practice where an injection of a standard is performed with the sole intention of determining if the chromatographic system is fit for purpose. The injection of trial samples is not acceptable, in part, because all data from analysis of product samples must be retained and reviewed (21 CFR 211.22, 211.165, 211.192, and 211.194). Furthermore, uncertainty about system performance may also suggest a potential insufficiency of the method&#;s design, validation status, analyst training, equipment maintenance, or other fundamental problem(s) in the laboratory that should be promptly corrected.
Column conditioning does not involve injecting a sample from a lot and is not considered a trial injection. When its use is scientifically justified, column conditioning should be fully described in the method validation package as to the conditions needed to make the measurement (i.e., based on data from the method validation) and should be clearly defined in an approved and appropriate procedure. Only validated test methods that demonstrate accuracy, sensitivity, specificity, and reproducibility may be used to test drugs (21 CFR 211.165(e)). Consistent and unambiguous injection nomenclature should be used, and all data from the column conditioning, including audit trail data, should be maintained and subject to review.
Therefore, FDA considers it a violative practice to perform a trial injection (including under the guise of column conditioning). FDA also considers it a violative practice to use an actual sample in test, prep, or equilibration runs as a means of disguising testing into compliance.
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Date: 8/12/ Back to Top
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