Contains Nonbinding Recommendations
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:
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.
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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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Ecommerce product filters are key tools to help your visitors discover products that meet their needs. But poorly optimized filters can drive visitors away from your site instead of securing more sales.
At The Good, we&#;re often amazed to discover product filters working against the business, not for it. The incredible part is that while fixing the problem takes focus and planning, it&#;s not all that difficult and can produce powerful results.
In fact, when smart filter design is in place, the user experience (UX) is pleasant and helpful. And if you carry more than a few items or product categories, filtered navigation is essential to helping your visitors narrow their product search.
In this article, we are going to explain the importance of using product filters, offer some filter design strategies, and show you how we helped one brand earn a 5.97% lift in conversions by optimizing their filters. If you&#;re an ecommerce manager or similar, this topic is essential reading.
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Product filters help visitors quickly sort through your product collection to zone in on products they need. Think of filters like tightly-focused, super-helpful search engines that guide visitors deeper into your product catalog. If a customer wants a red T-shirt, for instance, a proper filter would let them view a collection of products that meet the attributes of &#;T-shirt&#; and &#;red.&#;
But filters don&#;t just help visitors find products they already know they want. Filters are a key component of product discoverability, which is visitors&#; ability to browse, research, and choose products in a seamless, friction-less manner. This makes them an integral to marketing as well as to sales.
Let&#;s check out the definition of findability vs discoverability from Nielsen Norman Group:
&#;Findability: Users can easily find content or functionality that they assume is present in a website.
Discoverability: Users encounter new content or functionality that they were not aware of previously.&#;
So filters serve both of these key purposes. Users can both discover products they didn&#;t know they were interested in AND find what they are looking for depending on how they hope to use the site.
(The site search bar is another critical piece of product discoverability.)
What happens if your product filters are poorly optimized? Some visitors will fail to find products that meet their needs and leave your store. Ultimately, this will reduce your conversion rate and disrupt your bottom line.
Sadly, most ecommerce sites fail to use product filters well. According to research by the Baymard Institute, only 16% of major ecommerce sites provide a good filtering experience. 42% of those sites don&#;t have category-specific filter types for their main product categories and 20% lack thematic filters (season, style, etc.) despite selling products with obvious thematic qualities.
Look at Apple&#;s site, for instance. The homepage filtering at the bottom is rather plain and user-unfriendly. Would you say one of the world&#;s premier tech firms fails with filters?
How should you set up your product filters? It&#;s important to keep in mind that product filtering is contextual. The right combination of filters depends on your product catalog, visitor preferences, and other factors. Your combination of filters will be unique to your store.
For instance, if you sell lawnmowers, it makes sense to offer a filter for &#;yard size.&#; But that filter wouldn&#;t be appropriate on an ecommerce site that only sells pool toys. So to a certain extent, you&#;ll need to decide which product filters are right for your store.
That said, there are some common product filters that are appropriate on most e-commerce sites. These are the best filters for most stores:
Note: Those are just filters examples. You may not need them all.
One quick side point: The terms &#;filter&#; and &#;facet&#; are often used interchangeably, but it&#;s worth understanding the difference. &#;Filter&#; means to exclude items that don&#;t meet a criteria. Technically, if you select the &#;gaming PC&#; filter, you&#;re filtering out everything except gaming PCs.
&#;Facet&#; extends the idea of filters into something more complex that describes aspects of an object. Selecting several facets will return a list of results that meet all of those criteria. So if you select &#;gaming PC,&#; &#;1 TB storage,&#; and &#;Intel processor,&#; you&#;ll get a list of computers that have those three qualities.
Epicurious.com uses faceted navigation to let visitors combine filters. This search will return recipes for healthy dinner salads. This type of filtering is common and provides the best user experience.
Learn more: See Filters vs. Facets: Definitions by the Nielsen Norman Group.
Whether prospects searching your ecommerce site know exactly what they&#;re looking for or need some guidance, attention to these strategies will help make sure their experience on your site is geared towards helping them buy. We&#;ll also provide UX filter examples to illustrate the points given.
This is the number one rule for product filter design. The easier they are to identify and operate, the better your visitors will like them. Use filters that are reasonable and intuitive. Don&#;t create extra filters just to have more. It&#;s fine if you only need three or four.
Ecommerce filter design work can get complicated in a hurry. Plan yours carefully before you begin. Time invested here can pay off big in the development phase.
For instance, Zalora knows that sunglass buyers care about shape more than any other attribute, so they provide a filter to sort by shape and make it prominent in the filter menu.
A filtering system that makes sense to the design team may not play well in front of a live audience. Test early and test often. The sooner you catch problems, the easier they are to solve.
Learn more: Read our full guides on User Testing and A/B testing to learn how to measure the effects of your website and conversion rate changes.
What information do your customers need in order to make a wise purchasing decision? What do your customers desire? Do they favor certain colors over others? Do you see seasonal jumps in certain product attributes?
Solicit help from your staff, specifically customer service representatives, and your audience to prepare an exhaustive list of product attributes. Leverage your data as much as possible to discover what your customers care about.
Avoid industry jargon and branding terms. Your ecommerce product filters should be absolutely practical and common sense. Don&#;t make customers struggle to find exactly what they&#;re looking for.
Learn how to use the hidden psychological forces that shape online behavior to craft digital journeys that delight, engage, and convert.
Disney wants an age range filter for their massive collection of toys. They could list age groups (1-3, 4-6, etc.), but they know that assigning toys to rigid categories isn&#;t helpful and their customers tend to think in terms of &#;toddlers&#; and &#;kids.&#; So those are the words they use.
If a detail is important enough to be mentioned in the product description, it could serve as a filter. Price, brand, RAM, and internal storage are all key pieces of information that are definitely mentioned in the product descriptions of these phones, so they make perfect filters.
Items might be grouped around themes or use cases. These are called thematic filters and they help visitors quickly hone in on the desired product, especially when they&#;re in the early stages of their buying journey and don&#;t know exactly what they need. Macy&#;s does this well by letting you filter dresses by occasion.
Visitors may not wish to use the filter immediately, but the user experience is enhanced just by making the option available. This can be achieved by placing your menu of products filters at an even level with other objects on your category pages.
Your product filters should be different depending on the items they&#;re filtering. For instance, you wouldn&#;t need a filter for &#;screen size&#; on a category page of skateboards. The best filters are designed in groups around product categories so only appropriate filters are displayed.
Make sure the visitor receives visual confirmation that your ecommerce filter navigation is active. For optimum user experience, the current filter state (waiting for input, working, and output delivered) should be readily apparent.
Zappos distinguishes their active filters from their inactive filters with color. The &#;X&#; to cancel the filter is another indicator.
Many companies find the left side of the page best for ecommerce product filters. Others get better results on the right. You won&#;t know for sure until you test placement on your own ecommerce site. Never stop testing.
In this product filters example, note how Mastercraft has studied their information hierarchy from a UX perspective. Visitors can begin with a search, or they can choose from a top-level category that then drops down and opens up to further selections to get where they want to go quickly.
Don&#;t list all available filters if the options will overwhelm the visitor. Instead, use grouping in the displayed filter list to help shoppers keep moving along the sales path. Macy&#;s does it well again here. The filter groups (size, fabric, and color) are collapsible. The visitor only interacts with the groups that matter to them.
In some cases, it makes sense to offer different filters on mobile and desktop devices. For instance, you may want a stripped-down version for your mobile site that doesn&#;t include rarely-used options. Here again, testing will tell you when you are on target.
Learn more: Follow these 15 tactics to optimize your mobile experience and increase sales.
Page speed is always a critical factor. You lose 1% in online revenue for every millisecond your site delays in loading. Your product filters should sort and display the results quickly.
Learn more: Read our guide on page speed optimization to learn why speed matters and how to boost yours.
Leverage data from filters to help you better understand the desires of your customers.
High-traffic filters may serve visitors better by being moved up to a higher level in the scheme. This helps the visitor quickly focus on what they need. In this product filters example, ScotteVest opts for image-based filtering on the homepage.
Apple also does this well. Their top-level navigation helps the visitor get quickly to the category of choice. Navigation is often the first type of filtering.
Jump ahead of the competition by providing exceptional filtering as a user experience (UX) feature. Most ecommerce websites get a failing grade when it comes to the filtering experience.
First, audit your competition carefully. How do they use product filters? Do they make any critical mistakes? Do they filter products in a way you never considered before? Then implement the filters that make the most sense for your brand.
Always use filters on ecommerce sites with large product catalogs, but consider a filter even for stores without extensive product offerings. Anything you do to improve UX is good for your business.
For example, makeup brands like Epionce often have a limited selection of products, but they still have some categories for by concern like &#;dryness&#; and &#;anti-aging.&#;
Displaying the number of products in a filter helps the customer understand the size of that category and whether they should apply additional filters to make their search easier.
Home Depot includes quantities on each of its filters. When you select a filter, the new page contains updated quantities based on your current filters.
People really care about product reviews. This is a form of social proof and can draw purchases based on the feedback of others alone. So it deserves its own filter.
Home Depot does a great job here, as well. Their review filter lets you choose your bottom number. The results display everything above that threshold.
If a customer isn&#;t happy with the results of their filter combination, they may want to remove some filters to &#;open up&#; the sort. Give them a simple way to remove individual product filters.
In this product filters example, notice how House of Fraser turns each filter into a button that can be toggled off by clicking the &#;X.&#;
You definitely don&#;t want visitors to arrive on empty pages. If a filter won&#;t produce any results, it shouldn&#;t be an option. This means your product filters plugin, tool, or add-on should Work alongside your inventory management system. If a product&#;s inventory is zero, the associated filter should be hidden.
Just because a visitor applies a filter doesn&#;t mean they know exactly what they want. If they want to look at green and blue jackets, let them. Don&#;t force them to select one or the other. Notice how Zappos lets you filter by multiple shoe sizes.
Make it easy for the user to find all the current ecommerce product filters by listing them as an overview and in the filters menu. This gives them complete control over their experience.
Including a huge list makes for poor usability. Many visitors will dismiss it and move on to a site with less overwhelming navigation. Truncate your product filters and provide an expansion option. If a user wants to see the complete list, let them expand it with a selector.
Here again, choose your filtering plan according to the setup that will be most convenient for your customers. In this product filters example, Amazon offers filters that are relevant to that specific search query. If a customer searches for something, you can safely assume it&#;s important. (Also note the &#;See All 16 Departments&#; arrow to limit excessive options and cut down on confusion.)
We&#;ve given you a big list of actionable strategies to make your product filters more effective, but what does this look like in a practical sense? To help you understand, we&#;d like to walk you through a case study of how we helped one brand improve their conversion rate with smart product filters.
Fully is a direct-to-consumer brand that makes and sells office furniture They are known for their highly customizable products, such as the Jarvis standing desk.
The work-from-home boom of put Fully in a unique position. Demand for their products was high. The lead time on their popular standing desk was longer than usual, but the Fully team didn&#;t want to miss out on sales. They needed a way to display their in-stock products so as to encourage customers to buy something if they weren&#;t willing to wait for the desk.
All-in all, our job was to improve the browsing experience on Fully&#;s site to make other product categories more visible, thereby increasing the conversion rate and average order value.
We audited Fully&#;s analytics to identify conversion barriers, drop-off points in the customer journey, and where customers were coming from. We learned that there was room to improve exit rates from category pages and the add-to-cart rate on product pages.
Using heatmaps, we learned that customers like to engage with the filters located on category pages, particularly in regards to the different types of desks. This told us that customers who were unfamiliar with the brand didn&#;t understand the differences between the categories.
In order to improve Fully&#;s browsing experience on product category pages, we redesigned the product filtering system. We simplified the categories to help users navigate to specific types of desks. We also added functionality to filter by product materials and parts. Here&#;s the before and after.
This approach increased visibility for lesser-known products and gave users a focused way to navigate the site. The result was a 5.97% boost to the conversion rate on both desktop and mobile sites. The change produced a 75:1 return on investment for the client.
How did you do? Are you currently using many (or any) of the strategies in our list?
If you have a ways to go, don&#;t worry, you&#;re in good company. Like we said, only 16% of brands are providing a strong product filtering experience. And even if you already offer good filters, there&#;s always room for improvement.
But remember, you&#;re not improving these filters for the filters sake. Every one of these improvements means that you&#;re eliminating friction and making it a little easier for your consumers to purchase from you.
In short, the more you work to include these strategies, you&#;ll not only work your way into that 16% but you&#;ll also provide a killer user experience for your visitors and most importantly, you&#;ll drive even more conversions.
Not sure where to start? We know it&#;s frustrating to spend your money on traffic, but your revenue doesn&#;t change. At The Good, we help online businesses like yours remove all the barriers to conversion. Get in touch.
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Natalie Thomas is the Director of Digital Experience & UX Strategy at The Good. She works alongside ecommerce and product marketing leaders every day to produce sustainable, long term growth strategies.
For more information, please visit Industrial Filter Fabric.