A compliance issue that results from occasional inspectional observations, especially around aseptic processing, is time limitations or hold times for bulk drug products or sterile processing equipment and packaging components for product manufacturing. The citation typically states that a hold time designated by the manufacturer has not been justified.
With a lack of a clear definition of FDA expectations and industry standards, companies have difficulties justifying hold times. What tools do pharmaceutical companies have to establish hold times? Tools like Failure Mode Effects Analysis (FMEA), reliability engineering, process validation, container closure integrity testing, bioburden monitoring and product stability studies all may be useful.
What are the GMP requirements?
What do the GMP regulations say about hold times? 21 CFR 211.111 Time Limitations on Production states:
When appropriate, time limits for the completion of each phase of production shall be established to assure the quality of the drug product. Deviation from established time limits may be acceptable, if such deviation does not compromise the quality of the drug product. Such derivation shall be justified and documented (1).
The FDA expectations were further described in a 2004 guidance document. FDA’s Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice states:
When appropriate, time limits must be established for each phase of aseptic processing (§ 211.111). Time limits should include, for example, the period between the start of bulk product compounding and its sterilization, filtration processes, product exposure while on the processing line, and storage of sterilized equipment, containers and closures. The time limits established for the various production phases should be supported by data. Bioburden and endotoxin load should be assessed when establishing time limits for stages such as the formulation processing stage.
The 2004 guidance further states:
The total time for product filtration should be limited to an established maximum to prevent microorganisms from penetrating the filter. Such a time limit should also prevent a significant increase in upstream bioburden and endotoxin load. Because they can provide a substrate for microbial attachment, maximum use times for those filters used upstream for solution clarification or particle removal should also be established and justified (2).
Although these statements may indicate regulatory expectations, they provide little help to the manufacturer in setting actual time limitations.
Examples of Manufacturing Processes with Time Limitations
Based on regulatory expectations, time limits between individual unit operations must be established during the following types of operations:
- Drug product manufacturing, i.e., compressed tablet manufacturing (batching, blending, granulation, fluid bed drying, tablet compression, film coating, and packaging)
- Downstream processing during biopharmaceutical product manufacturing (centrifugation, affinity chromatography, viral inactivation, diafiltration and concentration, drug product formulation, sterile filtration, and aseptic filling)
- Generic sterile injectable product manufacturing (drug product formulation, sterile filtration, and aseptic filling).
The first step to take would be conducting a general risk assessment of the inherent stability of the product intermediate. Next, the data generated during process development and validation would be evaluated. Conducting a range study may help do this. With a multivalent process, using a statistical tool like Design of Experiments may be useful.
In tablet-making, there is more microbial contamination and chemical stability risk with wet granulations compared to dry granulations. Purified water is used as an ingredient with wet granulations and the production of coating solutions. Time limitations are usually established for the storage of wet granulation intermediate based on its water activity more than on water content. Similarly, coating solutions, especially those containing microbial growth supporting ingredients like gelatin, will require hold-time limitations.
With downstream processing of biopharmaceuticals produced from cell culture, cleaning and storage of chromatography resins, diafiltration and concentration equipment, and storage tanks should be emphasized. Holding in-process material at refrigeration temperature and bioburden-reduction filtration after every unit operation will discourage microbial growth.
A hold-time study protocol should contain all the appropriate study parameters for the material in question, the acceptance criteria for the analysis, the type of storage container, the volume of sample, the storage conditions, the frequency of sampling, the method of analysis and other required information. When justified, the study may be stimulated with smaller amounts of material—sufficient to simulate the storage conditions and to complete the tests—in smaller containers to conserve material. Typically, microbial test intervals would be in hours and chemical test intervals in days. A full discussion of process hold times related to bioburden and endotoxin has already been published (3).
Time limits the holding of bulk solutions prior to the filling operation, for example, storage in stirred, nonsterile product bulk tanks and sterile refrigerated jacketed bulk tanks should be considered. In fact, working with human albumin production at the New York Blood Center, the author experienced an increased frequency of bulk sterility failure related to longer storage after sterile filtration into large sterile stainless-steel tanks. This was related to the inherent unreliability of the steam sterilization of bulk holding tanks with their multiple valves, fittings and sampling ports. This bulk sterility problem was eliminated by introducing inline sterile filtration and aseptic filling.
Time limits for sterile filtration operations, especially for biopharmaceutical manufacturing, must be instituted. The ability for the product to support growth resulting in a higher challenge titer and potential filter grow-through with extended filtration times must be considered. The bulk material antimicrobial activity, viscosity, pH, temperature, bulk solution volume, filtration pressure, and filtration duration are all considerations in setting a time limitation consistent with the filter validation.
Setting time limits for holding sterile processing equipment and packaging components, for example, sterilized aseptic filling equipment, and sterile vials, stoppers and seals are a major challenge. These components may be wrapped in aluminum foil, stored in heat-sealed Tyvek® bags or sealed stainless steel containers, then sterilized and transported to the aseptic processing area. The loss of sterility is more likely to be due to a failure in the preparation prior to sterilization or damage during transportation than the length of the hold time.
Time limits for holding filled containers prior to terminal sterilization may depend on the use of aseptically filled vials versus non-aseptically fill vials for terminal sterilization. For example, if the aseptic filling step has been subject to process validation, that is, media fill, the process step will have a high sterility assurance, so the time limitation will be driven by the manufacturing schedule not the risk of microbial contamination. The reader is reminded that aseptically filled drug products may have a two- to three-year expiration dating, so setting a time limit to a few days makes little sense.
Time limits for holding in-process intermediates, like buffers, solutions and process aids, are not an economic constraint as they can be dumped and remade, but their unavailability for a process step may have a more serious scheduling impact.
Measurement of the Decline in Product Quality
Analytical tools are available to measure a loss in product quality. They include physical, chemical or microbiological degradation, such as a change in appearance, loss in container-closure integrity, particulate formation, drug substance degradation, pH drift, microbiological growth and endotoxin production.
Stimulated Hold-Time Studies to Justify Time Limitation
The question must be asked whether maintenance of sterility can be measured over time or if bioburden control can be simulated using laboratory cultures? These studies may result in too-conservative time limits.
Justification of Time-Limit Deviation
How can minor or gross deviation from the specified time limit be justified when the time limit selected is somewhat arbitrary? Why would holding a bulk biopharmaceutical drug substance for 24 hours be allowable but 25 hours would not? Is repeating a process step a reasonable response to exceeding the time limitation? The author recommends checking regulatory submissions to determine if repeating a step is considered a rework or not.
Avoidance of Holding In-Process Materials
Many strategies are being implemented to avoid the holding of in-process material. The drivers of these strategies are controlling risk, lowering manufacturing costs and shortening the manufacturing, time and decreasing in-process intermediate inventories, work-in-progress and prevent potential back orders. These strategies include continuous manufacturing, clean- and sterilize-in-place, and continuous sterile filtration and aseptic filling.
Is the application of reliability tools a useful approach? The American Society for Quality defines reliability as “the probability that a product, system, or service will perform its intended function adequately for a specified period of time, or will operate in a defined environment without failure” (4). This can be expressed mathematically as a probability as follows:
R(t) = Pr(T>t) = òt ∞ f(x) dx
Where f(x) is the failure probability density function and t is the length of the period of time.
However, although stochastic parameters may define and affect reliability, multivariate inputs with wide ranges of uncertainty largely invalidate quantitative methods of reliability, especially as applied to pharmaceutical drug products.
Using an argument based on reasonableness when setting a time limit may lead to compliance issues during a regulatory inspection. A better understanding of the industry position and regulatory expectations in terms of time-limit justification would be helpful. The author hopes that this article will advance this understanding.
- U.S. Food and Drug Administration. 21 CFR 211.111 Time Limitations on Production; U.S. Department of Health and Human Resources: Silver Spring, Md., 1978.
- U.S. Food and Drug Administration. Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice. U.S. Department of Health and Human Services: Rockville, Md., 2004.
- Sandle, T. Assessing Process Hold Times for Microbial Risks: Bioburden and Endotoxin. J GXP Compliance 2015, 19 (3), 1-9.
- Crossley, M. The Desk Reference of Statistical Quality Methods, Second Edition. ASQ Quality Press: Milwaukee, Wisc., 2007; 560 pp.