Conventionally, the term “overkill cycle" in validation of a steam-sterilization autoclave process is understood to mean that all items were steamed beyond all hope of anything surviving a grossly exaggerated load cycle. This cavalier approach to sterilization validation, however, is no longer enough to satisfy most regulatory inspectors, who have grown accustomed to control strategies based on risk assessment and scientific rational for the mitigation of the identified risks. A more robust, quality-by-design philosophy based in sound science and process understanding is more appropriate and defendable.

  A key component when presenting any autoclave validation package is to be able to clearly defend how the requirement to correlate biologic and physical lethality data from the validation reports is satisfied (1). Fulfilling this requirement can provide sound justification for autoclave critical process parameters (CPPs) and how they were validated.

 Development work to justify load parameters


When claiming overkill sterilization, one must be careful to have a good scientific rationale for the choice of cycle parameters. Just choosing the time and temperature on a cycle without detailed assessment does nothing to demonstrate control or knowledge of the critical operating parameters of the autoclave cycle or how those are affecting your particular load conditions. Theoretical values cannot be assured throughout a load before mapping with thermocouples is done to assure air removal and equilibration times support these assumptions.

 It is necessary to compare theoretical F

s (i.e., lethality levels) with the actual F

s delivered in an actual cycle. This real development testing will give a good idea of performance and capability of the autoclave and allow for realistic program-parameter settings. 

It may be appropriate to add some time or temperature as a safety factor to account for all of the variables inherent to autoclaving items needed in a manufacturing process. Unknown incoming bioburden load is a reasonable driver to choose an overkill sterilization cycle. However, gross overage indicates a lack of control of the process and a lack of understanding of the appropriate lethality being delivered to load items. Delivered lethality should be well understood from development runs and applied judiciously, even in overkill cycles, in order for validation to be a credible assurance of process functionality.

Fractional cycles as a method of validating overkill cycles

s throughout loads have been determined in development studies, program parameters may be defined for the autoclave cycles. At this stage, it may be appropriate to use fractional validation load programs, for which the validation cycle program delivers an F

 close to values needed to inactivate the BIs. The successful completion of this fractional cycle then gives a baseline to which a rational overage may be added for routine manufacturing cycles and justifies the term overkill (2).

 By defining a fractional (i.e., partial) cycle time and temperature for validation loads based on an understanding of the autoclave capabilities in conjunction with particular load limitations, an excellent rationale can be made, and manufacturing cycles can be programmed as overkill cycles. The overkill compensates for deviations in time or temperature caused by calibration faults in controlling thermocouples, chamber leaks, variability in packaging and assembling components, or other production events.


Any autoclave validation, for either overkill or product-specific load cycles, must demonstrate the delivered lethality to the most difficult locations using biological and physical data. More than being just a “dead or alive” reading, the bioindicator (BI) does enumerate delivered lethality when assessed appropriately. By knowing the D value of the BIs used and setting the fractional validation cycle to accommodate this value, inactivation can be achieved in the BIs and correlated to the thermocouple readouts. This validated cycle can then be appropriately increased to account for minor process variations to support a robust, validated process. This validation method, firmly based in the accepted tenets of sterilization science and a rational scientific approach, will provide a sound basis for an autoclave sterilization program. 

 Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing 

USP, General Chapter  <1211> "Sterilization and Sterility Assurance of Compendial Articles" (US Pharmacopeial Convention, Rockville, MD, 2013).

John Anderson is a quality assurance and validation professional with years of inspection experience. He can be reached at 

This article is excerpted from an article on defining and presenting overkill cycle validation, which will appear in the Troubleshooting column of the November 2013 issue of 

Articles

Troubleshooting

Parameters for steam-sterilization autoclave overkill cycles should be chosen based on process understanding.

Choosing Overkill Cycle Parameters

The North American market for drug-delivery technologies is projected to grow 8.9% per year through 2017, according to a report published by MarketsandMarkets (1). With such a positive forecast, it’s not surprising there is a constant flow of drug-delivery innovations involving metered-dose inhalers, needle-free injectors, autoinjectors, nasal sprays, transdermal patches, nebulizers, infusion pumps, drug-eluting stents, sustained-release formulations, ocular implants, and related packaging. Interest is particularly strong for dry powder inhalers, needle-free injectors, auto and pen injectors, orodispersible tablets, transdermal patches, and buccal transmucosal tablets, notes the report. 

Suppliers are boosting capacity to meet rising demand in North America and around the world. In January 2013, Catalent Pharma Solutions announced a $20-million investment in its Inhalation Center of Excellence in Research Triangle Park, NC. The project will expand production capabilities for clinical and commercial pressurized metered-dose inhalers. 

SHL Group (Sweden) is spending $40 million to expand production of autoinjectors and pen injectors in Taiwan. “Our customers are bringing more biologics to market,” explained Roger Samuelsson, chief executive officer of SHL, in a press release (2). SHL’s injector product range includes disposable and reusable devices with fixed or variable dosing, enhanced precision, and the ability to accommodate high-viscosity liquids. SHL also makes inhaler systems. 

The need to accommodate biologics with higher viscosities and patients with limited dexterity prompted Unilife to develop the Unifill Assure injector. An extended finger flange with a soft, rubberized, non-slip grip and an easy-to-press thumb button on a strengthened plunger improve ergonomics. Compatible with standard fill/finish lines, features include automatic user-controlled needle retraction. The automatic needle retraction eliminates the need for ancillary needle sheath-based safety products, ensures patients have an unobstructed view of the drug from any angle during all stages of use, reduces the risk of needlestick injuries or the aerosolization (splatter) of blood or tissue residue, and helps minimize the size of the injector and waste disposal requirements. Audible, tactile, and visual indicators simultaneously confirm full-dose delivery and activation of the retraction mechanism. After retraction the plunger locks preventing reuse or needle re-exposure. 

Ease of use is an important attribute for virtually all drug-delivery segments. For inhalation products, Aptar Pharma Prescription Division has developed the simple-to-use, easy-to-clean Twister dry-powder inhaler. Introduced at Pharmapack Europe, Feb. 13-14, 2013, in Paris, France, and also displayed at Pharmapack North America, June 18-19, 2013, in Philadelphia, the design improves access to medication as well as patient compliance. Molded and assembled in a class ISO 7 cleanroom at the company’s production facility in Suzhou, China, the device is suitable for early-phase clinical trials and for medication that treats asthma and chronic obstructive pulmonary disease. It works in three steps: insert, twist, and inhale. The twisting action crushes a capsule to release the drug. Patients can observe the processing of the capsule and powder through the transparent container and also receive audible and visual feedback confirming that the full dose has been properly delivered. 

MarketsandMarkets, “North American Drug Delivery Technologies Market (Metered Dose Inhalers, Needle-Free Injectors, Auto-Injectors, Nasal Sprays, Transdermal Patches, Nebulizers, Infusion Pumps, Drug Eluting Stents, Sustained Release, Ocular Implants) – Forecasts To 2017,” (Dallas, TX, July 2013).  

SHL Group, “SHL to Invest 40 Million USD in 2013 to Significantly Expand Production Facilities | Auto Injector, Pen Injector & Drug Delivery Devices,” Press Release, Feb. 22, 2013. 

Hallie Forcinio is Pharmaceutical Technology's packaging editor, 

Packaging

Capacity expansions and new products meet needs for inhaler and injector systems.

Drug-Delivery Market Growth Spurs Expansion and Innovation

A compact laboratory machine combines drying, granulating, and coating modules.     

The Solidlab 2 laboratory device from Hüttlin and Manesty, pharmaceutical process technology suppliers that have been part of Bosch Packaging Technology since 2011, combines several process steps in a compact, modular laboratory machine. Modules for drying, granulating, and coating in the fluid bed, as well as tablet coating in the coater, can be used individually or in combination. The laboratory device includes peripheral systems, such as inlet and exhaust air handling, sensor technology, and a control system.

A carrier provides shippers with the ability to move temperature-sensitive freight on dry-van carriers.     

CarrierDirect, which provides advisory services to logistics companies and carriers, partnered with One Stop Critical, which manufactures temperature-sensitive shippers and carriers, to launch the Critical Cube, a temperature-controlled carrier that holds a standard-sized pallet and has 77 cubic feet of loadable space. The Critical Cube allows companies to ship less-than-truckload (LTL) temperature-sensitive freight on dry-van carriers, eliminating the need to pay for a dedicated truck or to wait for a consolidated refrigerated-LTL carrier. The Critical Cube uses liquid carbon dioxide to maintain temperatures as low as -30 °F for up to five days. The technology is currently available for intra-California shipments, and will be introduced to other US geographies in late 2013 and early 2014. 

Featured products from Pharmaceutical Technology's monthly newsletter, Equipment & Processing Report

October 2013 Editor's Picks: Products from Bosch and One Stop Critical

Sterilization and disinfection are crucial processes for pharmaceutical manufacturing and are used in multiple aspects, such as materials, packaging, process equipment, isolators, medical devices, and cleanrooms. Steam and dry-heat sterilization are widely used for process equipment and for sterile drug products, but these processes can potentially degrade heat or moisture-sensitive materials.  Radiation sterilization, such as gamma radiation, avoids heat and moisture but can also potentially degrade materials. Ethylene oxide (EO) is an accepted and established chemical sterilization technology, but EO has safety hazards and potentially longer sterilization cycle times. Other technologies with advantages for certain applications are emerging. 


Vapor-phase hydrogen peroxide (VPHP) has been available for more than 20 years in the pharmaceutical industry and has been growing in use for various applications (e.g.,  decontaminating isolators, environments, process equipment, and material pass-throughs). Some problems experienced with implementing and qualifying VPHP can be addressed through a better understanding of the fundamental physiochemical characteristics of this sterilization method, such as its dual-phase (i.e., liquid and vapor) nature, according to a recent peer-reviewed article in 

 September issue by James Agalloco and James Akers (1). For example, VPHP may seem to have variability in lethality, but this result is largely due to adapting process models and approaches from a single-phase gas process (e.g., EO) without considering the two-phase nature of VPHP, said Agalloco and Akers. Advantages of VPHP are that it can be used with heat-sensitive materials and is compatible with most metals and plastics, it does not leave a long-lived residue, and it can have shorter cycle times in some cases.  

) gas generators are currently under development for isolator decontamination and cleanroom applications. The low boiling point of NO

 (21°C) reduces the amount of sterilant condensation that occurs on surfaces, which has been observed with some H

 processes, says Jim Rickloff of the Sterilization Technology Group. For rapid aeration at the completion of an exposure cycle, minimal condensation is an advantage. In the event that NO

 condenses or is adsorbed on a surface, it will evaporate much more quickly than will H

, explains Rickloff. Commercial sterilizers are currently available from Noxilizer for the terminal sterilization of medical devices and combination device-drug products and for the external surface sterilization of single-dose drug containers. An advantage of NO

 for sterilizing pressure or temperature-sensitive drug products is that, unlike EO and VPHP, the NO

 process operates at room temperature (2). 

) gas can be used for decontamination in a wide range of pharmaceutical manufacturing situations, from isolators or process equipment to cleanrooms and entire facilities. ClO

 gas is less corrosive than VPHP or liquid ClO

 gas, such as that used by ClorDiSys, does not contain impurities that can react to form corrosive byproducts, says Mark Czarneski, director of technology at ClorDiSys. ClO

 gas operates only in the gas phase and avoids some of the problems found with VPHP’s dual-phase operation; a ClO

 gas process has good repeatability and simple validation due to its real-time feedback and control capability. In addition, pure ClO

) is used in a precision cleaning and disinfecting process for medical instruments and devices, as well as in applications outside of life sciences. It can be used, for example, to clean the surfaces of silicone rubbers and polymers prior to bonding, coating, or assembly for use in stringent environments, such as cleanrooms, biomedical devices, or aerospace (3). The technology is currently being validated by the US NASA Jet Propulsion Laboratory for sterilization of equipment destined for Mars exploration, says David Jackson, president and CEO of CleanLogix. Although it is not currently used commercially in pharmaceutical manufacturing, the technology is capable of sterilizing pharmaceutical equipment or packaging components, says Jackson. The CleanLogix CO

 process can operate either as a liquid or supercritical fluid in a pressurized vessel or, in an ambient pressure environment, as a composite spray of solid CO

 crystals in an air stream. In liquid form, CO

 acts as a solvent to chemically remove particles, ionic contamination, and organic residues. As a spray, it physically scours the surface and also acts as a solvent to remove these materials. The composite spray can also be combined with an atmospheric plasma CO

 technique that further cleans the surface. In any of these techniques, trace amounts of ozone or peroxide can be added to the CO

 to kill microbes and denature spores. "A significant benefit of CO

 as a sterilization technique is that it can both clean and disinfect a surface," says Jackson. "Other processes leave behind debris, which can include biological endotoxins, but CO

 offers the capability to remove biological endotoxins."     


Industry experts James Agalloco and James Akers discuss 

Evan Goulet, technical applications manager at Noxilizer, discusses 

 for packaged parenteral drug products in the March 2013 issue of 

    
Industry expert John Anderson discusses 

 in an article in this October issue of the 

Production Trends

Vaporous hydrogen peroxide, nitrogen dioxide, chlorine dioxide, and carbon dioxide technologies can be used in pharmaceutical manufacturing to sterilize or disinfect.

Equipment and Processing Report-10-16-2013

Choosing Overkill Cycle Parameters

Drug-Delivery Market Growth Spurs Expansion and Innovation

October 2013 Editor's Picks: Products from Bosch and One Stop Critical

Emerging Sterilization and Disinfection Technologies Offer Alternative Solutions