By Richard J. Forsyth,Alain Leblanc,Mark Voaden
A well run cleaning-validation program requires a significant amount of planning and resources. Planning takes into account the size, configuration, and complexity of the manufacturing equipment; the physical properties of the soils encountered, which directly affect the cleaning procedure used; the detergent to clean the equipment; the type of swab or rinse sampling to capture residue levels; the analytical test methods to determine residue levels; the periodic monitoring of the system to ensure ongoing compliance; change control to address new residues and equipment; appropriate documentation; and training for personnel cleaning equipment and performing validation challenges. Required resources include equipment downtime for the validation, raw materials for the formulations tested, analytical instrumentation for analysis, detergents for cleaning, solvents for testing, and personnel to perform the validation.
The entire cleaning-validation program and its execution depend directly on the acceptable residue limit (ARL) for the formulation residue. The active pharmaceutical ingredient (API) residue is monitored because it is the most phamacologically active component of the formulation. The ARL established for a program must be scientifically justified on the basis of the needs and capabilities of the manufacturing facility. In its Guide to Inspection of Validation of Cleaning Processes (1), the US Food and Drug Administration stated that residue limits should be logical, practical, achievable, and verifiable. The agency did not intend to set acceptance limits for validating cleaning processes. One of the examples cited as a possible residue limit used in industry, however, was 10 ppm of carryover into the subsequent batch manufactured.
The purpose of cleaning validation is to prevent the cross-contamination of a drug formulation. The primary concerns of cross-contamination are an evaluation of the therapeutic-dose carryover or the toxicity of the potential contaminant. Any contaminant is undesirable, but one with a pharmacologic or toxicological effect is far more serious. The Food, Drug, and Cosmetic Act (2) states: "A drug ... shall be deemed to be adulterated if it consists in whole or in part of any filthy, putrid, or decomposed substance," that is, something that will cause an adverse pharmacological effect. This definition supports the pharmacological and toxicological concerns.
If, however, the amount of a residue is below the level at which it would have an unintended, adverse health effect, what is the allowable level from an adulteration standpoint? Should a health-based limit be the only limit for equipment cleaning? Should the analytical-method detection limit be the standard (3)? Or, if an intermediate adulteration limit exists, what rationale determines that level? In the past, analytical methodology had limited sensitivity, making health-based and adulteration-based contaminations essentially equivalent. The increased sensitivity of analytical methodology seemingly has created a contradictory situation. Modern analytical detection limits are far lower than the pharmacological levels of drugs, thus creating a divergence between the previously equivalent health-based and adulteration definitions.
A logical residue limit would be one that demonstrates no pharmacological or toxicological effect, without regard to analytical sensitivity. This would indicate that residue levels can be as high or as low as the health-based limit will allow. This approach, however, would allow equipment to be visually dirty for relatively safe residues, which indicates an inadequate cleaning procedure. A logical residue limit also should leave the equipment visually clean. Setting residue limits any lower than the health-based and visible levels does not appear to be necessary or logical and adds no additional value to the cleaning process.
Several cleaning-validation programs use the dual health-based–adulteration-based criterion (4–6). Evaluations based on toxicity, tablet weight, number of doses administered, swab recovery, swab area or equipment surface area, and batch size determined the ARLs from both an adulteration-based and health-based perspective. The lower of the two limits was the designated ARL for the formulation and the equipment.
The cleaning-validation program in our pilot-plant facility calculated ARLs for both the health-based and adulteration-based criteria and used the lower of the two (7). The dynamic nature of the pilot plant and the drug-development process necessitated regular re-evaluation of the ARL for each API. Each API required a health-based evaluation, but the majority of development compounds had such low toxicity that their adulteration limits were lower. A proposed alternative to the constant re-evaluation of adulteration limits was to use a constant adulteration limit of 100 μg/25 cm2 swab or 4 μg/cm2 . This technique would streamline the cleaning process and minimize potential errors without compromising quality or safety.
Health-based risk assessment
To implement an adulteration limit, it must be lower than the associated health-based ARL. The adulteration limit would be lower at the level at which compounds are not likely to be potent, highly toxic, or carcinogenic. A corresponding allowable daily intake (ADI) for this category of material is 100 μg/day (0.1 mg/day) (8).
The calculation for the health-based ARL with an ADI of 0.1 mg/day includes:
in which ADI is the allowable daily intake for the compound, SSA is the shared product-contact surface areas of the manufacturing equipment train, and recovery is the percentage of spiked material recovered for assay.
Table I: Calculated health-based acceptable residue limit (μg/swab).
Table I shows the health-based ARLs with associated parameters for an ADI of 0.1 mg/day, tablet weight from 0.1–1.5 g and maximum daily dose from 1–10 tablets. The number of tablets per batch ranged from 266–10,000 (small) to 3600–160,000 (medium) to 46,666–1,000,000 (large), based on batch sizes of 0.4–1 kg (small), 5.4–16 kg (medium), and 70–100 kg (large), respectively. It was assumed that the next batch was manufactured in equipment with the same SSA.
The shaded portions of the small, medium, and large batch ranges in Table I fell below the proposed limit of 100 μg/swab (4 μg/cm2 ). The low end of each range assumed the smallest batch size, the largest tablet weight (1500 mg), and the highest number of tablets dosed (10).
In the pilot plants, about 5% of manufactured batches fell below the 100 μg/swab (4 μg/cm2 ) limit. The batches that fell below the 4 μg/cm2 limit were typically for clinical studies with large tablet sizes (>1000 mg), multiple-tablet doses (>6 tablets/dose) or small batch sizes (<500 g). Small batch sizes generally are for first-in-man studies or preclinical and Phase I studies. These clinical-trial programs are dosed on small populations to establish dose levels.
The risk of falling below the 4 μg/cm2 limit for compounds with ADIs >100 μg/day was small, based on the site data. Also, of the 1225 swab samples taken in support of cleaning validation, none failed the ARL for the compound tested, greater than 98% of the swabs were below 1 μg/cm2 , and more than 99.5% were below 4 μg/cm2 , further reducing potential risk.
Finally, a continuing program for monitoring cleaning effectiveness using visible residue limits (VRL) was conducted. Of the manufactured batches that fell below the 100 μg/swab (4 μg/cm2 ) limit, the highest VRL was 1.23 μg/cm2 , which is well below the health-based limit. Therefore, for compounds with ADIs >100 μg/day, it is extremely unlikely that the adulteration limit selected will be greater than the health-based limit.
Adulteration-based calculation
The adulteration limit was used when it was lower than the health-based limit. For development compounds in the pilot plant (7), the adulteration limit originally was calculated using the following equation:
in which UAL was the upper acceptance limit; SSA the shared surface area, MBS the minimum batch size for the equipment train, and recovery the fraction of spiked material recovered for assay. The UAL of 10 μg/g (10 ppm) cited by FDA (1) was used in various cleaning-validation programs (3, 9, 10). The SSA was the combined product-contact surface areas of the manufacturing equipment train. The MBS provided the most conservative limit because any residue would be most concentrated in the subsequent batch. The swab area of 25 cm2 was used widely (3, 7, 11, 12) in industry.
Calculation of an allowable adulteration level was a logical cleaning limit for a pilot plant but in the long term proved to be impractical. The number of factors that went into the pilot-plant production schedule, the drug-development formulations, and the residue determination made an adulteration assessment a constantly changing number.
Pilot-plant issues
Number of pilot-plant programs. The pilot plant manufactured varied formulations of numerous compounds. The programs in the pilot plant increased with new compounds and decreased as programs ceased development or were transferred to commercial manufacturing. Schedulers, formulators, equipment cleaners, analytical chemists, and quality personnel were involved. The number of programs and personnel along with the associated ARL calculations, documentation, and communication made it difficult to maintain a consistent, compliant program.
Number of new compounds. The number of new compounds entering the pilot plant was significantly greater than the number of new compounds entering a commercial manufacturing facility. These new programs had to be included in the overall cleaning-assessment program. Validating a new compound required significant analytical method development and validation. In addition, the small, early-phase manufacturing equipment was in great demand, and extended downtime for cleaning validation support was problematic.
Subsequent product. The manufacturing schedule in the pilot plant was variable. Equipment was scheduled for use several weeks in advance, but other programs sometimes took priority. Even knowing the subsequent product was no guarantee that a particular formulation was the same as the previous one manufactured for the product. Calculating an ARL based on the subsequent product manufactured in the equipment was problematic.
Current equipment train versus subsequent equipment train. The equipment train was the order in which equipment was used to manufacture a formulation. Blending, granulation, roller compaction, drying, and tablet pressing were examples of unit operations that together manufactured a clinical formulation. The ARL calculation for the equipment train assumed that the same train was used for the subsequent product. This almost never was the case in a pilot plant, which made the value of the ARL limited. An alternative ARL calculation considered each individual piece of equipment without regard to the manufacturing train. This type of ARL consideration became exceedingly cumbersome without adding increased value to the ARL process.
Formulation-development issues
Formulation changes. The formulation for each research compound evolved during development. A dry-filled capsule for a Phase I compound became a film-coated tablet in Phase II. Refinements in formulation composition also were common. Excipient levels changed to optimize the physical properties of the formulation. Formulation changes also resulted from scale-up issues. Formulation modifications often changed the ARL for the subject compound.
Establishing effective dose. The effective dose of an API was unknown when clinical trials began. Dose levels could cover several orders of magnitude for early clinical trials. The results of the ongoing trials determined the dose for the next phase of testing and the eventual market-dose level. Formulations of early-development compounds had different dose levels and batch sizes. The amount of API in a formulation had a direct effect on the ability to clean the equipment. Therefore, cleaning could be assessed after every batch, based on the API factors involved.
Scale-up. Each clinical trial required a larger batch size than the previous trial, which necessitated equipment with a larger capacity. The physical interactions of the formulation components for larger batches often resulted in changes to the formulation or required a different type of manufacturing equipment. Each time the batch size or the equipment train changed, the ARL was reassessed.
Adulteration-determination issues
Effect of small batch size or unit operations. In the pilot-plant environment, initial batch sizes were very small, often on the order of several hundred grams. Calculating an ARL based on the smallest batch size reduced the cleaning limit to a low level and potentially affected a Phase II compound manufactured just before a Phase I compound. Similarly, calculating an ARL for each individual piece of equipment in the manufacturing train resulted in very low cleaning limits for small surface-area equipment.
Rather than calculate the ARL for every clinical batch manufactured, certain assumptions were made to generalize the equation. The most conservative assumption used the minimum batch size for the equipment. This assumption made the generalized ARL lower than a specifically calculated ARL under most circumstances.
The adulteration limit calculation was the following:
Table II: Product-contact surface areas (SSA) for typical equipment trains by phase.
Table II shows the product-contact surface areas for a typical equipment train for Phase I (small), Phase II (medium), and Phase III (large) formulations. Table III shows the range of ARLs for a constant UAL of 10 μg/g, a swab area of 25 cm2 , and a recovery of 100%. The calculated adulteration limit varied from 17 to 216 μg/swab for the same compound, depending on the manufacturing train. The adulteration limit varied from batch to batch for the same compound, making reassessment a routine occurrence.
Table II: Product-contact surface areas (SSA) for typical equipment trains by phase.
The variable adulteration limit also brought into question the value of the calculated limit to the overall cleaning program. For small batches, the limit was far below the 10 μg/g level. For larger batches, the calculated adulteration limit was greater than the visually clean level, thus making it obsolete.
Analytical limits. High-performance liquid chromatography and total organic carbon methods were used most frequently. Each analytical test method had very low detection limits, either in the ppm or ppb range. Analytical limits were lower than the calculated health-based and adulteration-based limits. On the basis of instrumental capabilities, the use of analytical limits was considered for the adulteration limit.
Using 0.1% of the subsequent API as the adulteration limit was not appropriate. The 0.1% limit, determined during release testing, was intended for qualifying impurities that were associated with the manufacturing process or related compounds, and not for extraneous impurities caused by cross-contamination. Acceptance limits should reflect the capability of the cleaning processes (13).
Visible residue limits
The determination and use of VRLs demonstrated that the vast majority of formulations and APIs had VRLs lower than 100 μg/25 cm2 swab (4 μg/cm2 ) (14, 15). Of the 54 formulations evaluated to date, all were well below 100 μg/25 cm2 swab. Of the 102 APIs, excipients, and detergents evaluated, only five excipients and one API had VRLs greater than 100 μg/25 cm2 swab. Limited applications of VRLs have saved resources without sacrificing quality (16, 17).
Swab area. An often cited adulteration limit was 10 ppm or 100 μg/swab, using a swab area of 25 cm2 for cleaning validation. This amount was a feasible limit. The swab area was not as important as the scientifically justified limit but was a practical compromise to obtain a representative residue sample against the occasional need to swab smaller pieces of equipment.
Conclusion
The factors that affect the adulteration calculation made it an impractical situation for a pilot-plant application. A constantly changing adulteration limit caused documentation problems and made compliance difficult to enact and enforce.
An alternative single adulteration limit was proposed for compounds with ADIs >100 μg/day. An adulteration limit of 100 μg/25 cm2 swab (4 μg/cm2 ) was satisfactory as long as the equipment was visually clean. This limit ensured that there were no toxicity cross-contamination problems and that the equipment was visually clean. A single, scientifically determined adulteration limit is logical, practical, achievable, and verifiable, making it a justifiable adulteration limit for a pilot-plant facility.
Richard J. Forsyth* is an associate director in global clinical GMP quality with Merck & Co., Inc., WP53C-307, West Point, PA 19486, tel. 215.652.7462, fax 215.652.7106, richard_forsyth@merck.com [richard_forsyth@merck.com]
Alain Leblanc is a facility manager at Merck Frosst Canada's Center for Therapeutic Research. Mark Voaden is head of service for validation and compliance for facilities with Merck, Sharp & Dohme in the United Kingdom.
*To whom all correspondence should be addressed.
Submitted: June 20, 2006. Accepted: Aug. 24, 2006.
Keywords: adulteration limit, cleaning validation, compliance, pilot plant.
References
1. US Food and Drug Administration, Guide to Inspection of Validation of Cleaning Processes, (Rockville, MD, Office of Regulatory Affairs, 1993).
2. Food, Drug and Cosmetics Act, Chapter V, Section 501(a)(1), 1938.
3. FDA, CDER Human Drug CGMP Notes, 9 (2) (Rockville, MD, Division of Manufacturing and Product Quality, Office of Compliance, Center for Drug Evaluation and Research, 2001).
4. G.L. Fourman and M.V. Mullen, "Determining Cleaning Validation Acceptance Limits for Pharmaceutical Manufacturing Operations," Pharm. Technol. 17 (4), 54–60 (1993).
5. A.O. Zeller, "Cleaning Validation and Residue Limits: A Contribution to Current Discussions," Pharm. Technol. 17 (10), 70–80 (1993).
6. K.M. Jenkins and A.J. Vanderwielen, "Cleaning Validation: An Overall Perspective," Pharm. Technol. 18 (4), 60–73 (1994).
7. R.J. Forsyth and D. Haynes, "Cleaning Validation in a Pharmaceutical Research Facility," Pharm. Technol. 22 (9), 104–112 (1998).
8. D.G. Dolan et al., "Application of the Threshold of Toxicological Concern Concept to Pharmaceutical Manufacturing Operations," Regul. Toxicol. Pharmacol. 43 (3), 1–9 (2005).
9. R. Baffi et al., "A Total Organic Carbon Analysis Method for Validating Cleaning Between Products in Biopharmaceutical Manufacturing," J. Parenter. Sci. Technol. 45 (1), 13–19 (1991).
10. R.J. Romanach et al., "Combining Efforts to Clean Equipment in Active Pharmaceutical Ingredient Facilities," Pharm. Technol. 23 (1), 46–58 (1999).
11. M.A. Stege et al., "Total Organic Carbon Analysis of Swab Samples for the Cleaning Validation of Bioprocess Fermentation Equipment," BioPharm 9 (4), 42–45 (1996).
12. D.A. LeBlanc, "Establishing Scientifically Justified Acceptance Criteria for Cleaning Validation of Finished Drug Products," Pharm. Technol. 22 (10), 136–148 (1998).
13. FDA, CDER Human Drug CGMP Notes, 6 (2), 5–6 (Rockville, MD, Division of Manufacturing and Product Quality, Office of Compliance, Center for Drug Evaluation and Research, 1998).
14. R.J. Forsyth, V. Van Nostrand, and G. Martin, "Visible Residue Limit for Cleaning Validation and its Potential Application in a Pharmaceutical Research Facility," Pharm. Technol. 28 (10), 58–72 (2004).
15. R.J. Forsyth and V. Van Nostrand, "Application of Visible Residue Limit for Cleaning Validation in a Pharmaceutical Manufacturing Facility," Pharm. Technol. 29 (10), 152–161 (2005).
16. R.J. Forsyth and V. Van Nostrand, "Using Visible Residue Limits for Introducing New Compounds into a Pharmaceutical Research Facility," Pharm. Technol. 29 (4), 134–140 (2005).
17. R.J. Forsyth, J. Hartman, and V. Van Nostrand, "Risk-Management Assessment of Visible-Residue Limits in Cleaning Validation," Pharm. Technol. 30 (9), 104–114 (2006).
Table I: Calculated health-based acceptable residue limit (μg/swab).
Table II: Product-contact surface areas (SSA) for typical equipment trains by phase.
Table II: Product-contact surface areas (SSA) for typical equipment trains by phase.
Sunday, December 12, 2010
Understanding Overkill Sterilization: An End to the Confusion
By James P. Agalloco
The author clarifies the definition and objectives of overkill sterilization for steam sterilization cycles. Current sterilization practices are reviewed and the validation difficulties associated with the various definitions of overkill sterilization are explored.
The overkill method is perhaps the most common method used in the development and validation of sterilization processes. Overkill sterilization primarily is applied to the moist-heat processing of materials, supplies, and other heat-stable goods. It generally is considered to be the simplest and most straightforward method for the design and validation of moist-heat sterilization processes. Although this is true, there is substantial confusion about how to use the overkill method and, in fact, regarding what actually constitutes an overkill process. Confusion associated with the overkill approach exists in all of the widely used sterilization technologies; that is, moist heat, dry heat, gas, and radiation. This article focuses on steam sterilization, of which there is both a greater amount of published definitions and a more precise and generally accepted understanding of the underlying science.
A contemporary definition of overkill moist-heat sterilization follows: "This is usually achieved by providing a minimum 12-log reduction of microorganisms having a D-value of at least one minute at 121 °C" (1). This is a simple-enough definition. Unfortunately, it cannot be demonstrated in a straightforward manner with presently available technology. What this definition suggests is that overkill requires a 12-D process, which equates to lethality sufficient to deliver a 12 × D 121 lethality level. This is not a lethality standard at all, however, because it inappropriately links the process lethality requirement to the characteristics of a specific biological indicator (BI). This article reviews present sterilization practices and explores the difficulties inherent in this definition.
Sterilization basics
Sterilization as a process can be rather simply defined as:
a validated process used to render a product free of viable organisms. In a sterilization process, the nature of microbiological death or reduction is described by an exponential function. Therefore, the number of microorganisms which survive a sterilization process can be expressed in terms of probability. While the probability may be reduced to a very low number, it can never be reduced to zero (2).
Figure 1
The difficulty lies in demonstrating the effectiveness of that process. The death of microorganisms by any sterilization method has been shown to generally follow a straight line termed the "death curve" (see Figure 1).
Figure 2
This phenomenon occurs with all microorganisms and is not restricted to any particular species. The slope of this line represents the resistance of the microorganism to the sterilization process. The death curve for organisms exhibiting substantial resistance will have a shallow slope, and those with low resistance to the sterilization process will have a much steeper slope (see Figure 2).
The difference in microbial resistance is critical to sterilization validation. The microbial genera Geobacilli, Bacilli, and Clostridia, having substantial resistance to the sterilization process, are commonly chosen as BIs to provide an appropriate evaluation of the process. These BI organisms are stipulated to be spore populations that have much higher resistance to sterilization processes than the vegetative cells that predominate in the normal microflora found in pharmaceutical production environments. Using these spores as indicator organisms creates a process challenge that is inherently worst-case. In the case of moist heat in which sterilization conditions are very well defined and understood, BIs are best used to establish that there is sufficient correlation between physically measured lethality, generally in the form of thermometric data, and biological lethality measured using calibrated BIs.
Sterilization processes are designed using one of three basic approaches (including the overkill method), each of which requires some degree of knowledge of the resistance and population of the bioindicator and bioburden (1). The bioburden method requires detailed knowledge and control over the bioburden resistance and population. The bioburden/biological indicator (BB/BI) method relies on the difference in resistance of the bioburden and BI (see Figure 2). With information about and control over the bioburden population and resistance, sterilization cycles requiring less time and temperature (relative to the overkill method) can be used successfully. Both of these methods allow for lower heat input to the materials being processed (an important consideration for terminal sterilization of filled product containers or the sterilization of in-process fluids and laboratory media), provided that increased attention is paid to presterilization bioburden.
The overkill method relies upon the selection of a lethality level known to be adequate to ensure sterilization without routine control over bioburden. A delivered F 0 of 12 min is an example of an overkill level of lethality. The basis for this level is that if the bioburden on an article were one million and all of that bioburden consisted of resistant spores with a D 121 value of 1 min, then a 10–6 probability of a nonsterile unit (PNSU) would be consistently attained. Obviously, this reflects worst-case assumptions regarding both the bioburden level and resistance, which would in every instance be lower in the real-world condition. The role of the BI would be to prove that there is a strong correlation between a physically determined F 0 of 12 min and biological lethality at the location of the indicator. A good correlation between biological and physical lethality ensures that an efficient and well-designed cycle with suitable steam penetration and air removal (where necessary) exists.
If understanding of overkill sterilization were all that is needed, this effort would be complete. The difficulty lies in validating overkill sterilization in a manner that is easily defendable to those unfamiliar with sterilization science and realistic in its execution. The first and simplest step is to define the minimum process objective for the sterilization process. The objective is the universal maximum probability of a single nonsterile unit (PNSU) in 106 units (a PNSU of 1 × 10–6 for any individual item). This is nothing more than an acceptable risk of contamination, whose origin (in the food industry) goes back many years. This criterion is the same for all sterilization processes, regardless of the sterilization method or the cycle approach used. The expectation is that the routine process will achieve the desired PNSU and that the routine process requirement does not apply to the validation effort. If that were not the case, then there would be no difference in the cycle approaches. The intent is always to establish the process such that it provides the same minimum confidence in the sterilized materials regardless of the varying controls defined.
Definitions of overkill cycles
Table I: Definitions of overkill sterilization and assessments of the validation difficulties for each.
The difficulties with overkill sterilization begin at this point. What is an overkill process? Including the currently prevalent definition of overkill given previously, there are various definitions, each of which satisfies the base requirement of a maximum PNSU of 1 in 10–6 but with varying process requirements. These definitions are presented in Table I, including assessments of the validation difficulties associated with each. It should be immediately evident, that the definitions are nonidentical, and thus the process required to achieve overkill is not constant for the various methods. The differences and difficulties associated with the varying definitions is a problem of some magnitude and is the main reason this article was developed.
What should be immediately evident is that the various definitions of overkill, and thus the validation of overkill sterilization for moist-heat processes, lack consistency. Simply put, demonstration of overkill is variable depending upon the regulatory or compendial expectations. Perhaps most unfortunate of all, none of the definitions include a requirement for nor provide a means to directly support a PNSU of 1 in 10–6, which is something every sterilization process is expected to achieve.
The half-cycle method
To support the minimum PNSU, some practitioners adopt the half-cycle approach in which a 106 population of a resistant indicator is inactivated during the validation effort, and then the exposure period is doubled in routine operation. It relies on simple mathematics. Killing a BI with an initial population of 106 in the half-cycle validation study means at least a 9-log reduction has been attained. (A routine sterilization cycle with double the exposure period projects to >18-log reduction). This assumes the bioburden is identical in count and resistance to the BI, which is virtually impossible in the real world. The PNSU for a typical bioburden microorganism using this approach could easily exceed 10–200 or greater (see Table II for an example of half-cycle using an 8-min validation cycle and 16-min routine cycle with an initial microbial population of 106).
Figure 3
Figure 3 represents this process and the effect on the BI microorganism. (The D 121 value of the BI in Figures 3–6 is approximately 1 min.) The slope of the death curve, which depicts the number of surviving microorganisms at a time point, is known precisely only during the survivor-curve region where the number of survivors can be readily determined. The numbers of potentially surviving BI organisms in the fraction-negative region can be estimated using various methods requiring multiple challenge units exposed at cycles where some but not all of the BIs are rendered sterile. Extension of the death curve below a survival probability of 1 × 10–2 to 1 × 10–3 assumes that the death curve is logarithmically linear. This is a reasonable assumption because microbial death follows essentially first-order kinetics.
The confirmation of a 1 × 10–6 PNSU using any microbial challenge available can only be assumed, but it can be assumed with a high degree of confidence based upon biological lethality data. This salient point must be accepted without question. Irving Pflug has explained, "Accept that while the objective of a sterilization process may be a PNSU of 10–6, we cannot directly measure microbial levels of less than one surviving microorganism in 10 to 100 units (from 10–1 to 10–2). Therefore when designing or validating sterilization processes, we use indirect methods, so we have real measurements that are equivalent to our nonmeasurable PNSU of 10–6" (9).
Figure 4
In a sterilization validation study using an initial BI population of 106 spores per indicator, 20 strips per study, and three replicate runs in which no survivors are observed, the log reduction demonstrated requires approximately 9 logs (106 × 20 × 3 = 6 × 107 reduced to zero survivors) (see Figure 4).
Figure 5
If this process is considered the half cycle, then the full cycle (with twice the exposure time) is depicted in Figure 5.
Because the lethality of the full cycle cannot be demonstrated using a biochallenge and recalling that a 106 BI challenge is destroyed in the half cycle, the log reduction delivered to the BI must be assumed. Using the assumed log reduction for the half cycle and doubling the dwell time, the log reduction for the BI in the full cycle can be estimated at 18 logs and easily meets the overkill definition of a minimum 12-log reduction of a BI with a D-value of 1 min (assuming the BI had a D 121 > 1 min) as is typical in nearly all overkill validation studies.
Figure 6
There are several inherent assumptions with the half-cycle method. The first assumption is that the bioburden would be as numerous and resistant as the BI. Second, it is assumed that the complete destruction of the multiple BIs in triplicate studies demonstrated a 9-log reduction of that BI. Finally, the death curve of the BI is assumed to be linear in a region where it cannot be experimentally determined.
Sterilization process objective
The routine sterilization of items in any sterilization process is intended to destroy the bioburden microorganisms that might be present on or in the materials being processed, regardless of their initial population and resistance. The goal is constant: to attain a minimum PNSU of 10–6. Consider the following definition of overkill sterilization as being consistent with what process expectations should be:
Overkill sterilization is a process where the destruction of a high concentration of a resistant microorganism supports the elimination of bioburden that might be present in routine processing. That objective can be demonstrated by attaining any of the following: a defined minimum F 0, a defined time-temperature condition, or a defined log reduction of a biological indicator.
This definition reflects the process requirement directly, with full recognition that bioburden organisms typically have minimal heat resistance. Destruction of the BI in high concentration requires time and temperature conditions far in excess of what is required to destroy the bioburden, and thus overkill is demonstrated.
Demonstrating a minimum PNSU of 1 × 10–6 for a sterilization process can be ensured only where the number and resistance of the microorganisms present on or in the items being sterilized is known. This can be accomplished definitively using any of the sterilization-cycle approaches described previously, and delivering that lethality is not restricted to the overkill method. It is supported by information about the relative resistance of the bioburden to the biological indicator in the BB/BI method in which partial kill of the indicator is sufficient to support the required minimum PNSU for the bioburden. With the overkill method, complete destruction of the resistant BI in high numbers is more than sufficient to ensure the minimum PNSU for any conceivable bioburden.
In everyday usage of sterilizing equipment, the BI is not present. The process is expected to confidently destroy the bioburden. In today's industry, we have numerous controls on the pre-sterilization bioburden, and in many instances, especially terminal sterilization, it is monitored for each sterilizer load.
Table II: Log reduction and PNSU in selected cycles.
If we were to make a worst-case bioburden assumption, it might be a maximum of 1000 CFU of a resistant sporeformer such as Bacillus subtilis or Bacillus atrophaeus. These mesophilic sporeformers are occasionally found in pharmaceutical plants during environmental monitoring and bioburden sampling. The maximum reported D 121 for these species is <0.5 min. It should be immediately evident from Table II that the 8-min validation (the half cycle) cycle achieves the maximum PNSU that exceeds the 1 in 10–6 expectation for any microorganism with D 121 ≤1 min. For the assumed bioburden of 0.5 min, the log reduction in the half cycle relative to a BI with D 121 = 1 min is greater than 18 logs. The half-cycle process will reproducibly attain the universal expectation of a minimum PNSU on 1 × 10–6. For bioburden organisms that are not sporeformers, the level of safety is even greater (see Table II).
Overkill sterilization is thus attained for bioburden microorganisms (even those with substantial resistance) in relatively short cycles without the need to double the cycle. The excessive heat input necessary to use a half-cycle approach should not be considered benign. Elastomeric closures, tubing, filters, gasket materials, hoses, and other materials that are commonly sterilized using the overkill method can all suffer adverse effects as a consequence of extended sterilization times. Obviously, the half-cycle approach should never be used for heat-sensitive materials, as it almost always results in unnecessary degradation of the material being processed.
Although the half-cycle method might seem acceptable to some, it strikes this author as an overly conservative approach that belies the customary industry controls on bioburden. There is little, if any, scientific rationale for its continued use in steam sterilization. Requirements for environmental monitoring, cleaning validation, bioburden monitoring, and component preparation all serve to ensure that presterilization bioburden will approach neither the population nor the resistance of the biological indicator. If resistance and count are within reasonable control—that is, being nonthermophilic and meeting the local environmental limits—then any of the alternative approaches can be used.
Conclusion
Process expectations for demonstration of a minimum PNSU of 10–6 are essentially universal. Overkill sterilization in its many variants is only one means of demonstrating that minimum expectation. Its demonstration for routine processing relies on either knowledge or assumptions regarding the bioburden number and resistance and little else. As the challenge microorganism is not present in routine sterilization, only information about the bioburden is relevant to establishment of the desired PNSU.
James Agalloco is president of Agalloco & Associates, PO Box 899, Belle Mead, NJ 08502, tel. 908.874.7558, jagalloco@aol.com [jagalloco@aol.com]
He is also a member of Pharmaceutical Technology's Editorial Advisory Board
Keywords: Sterilization
References
1. PDA, Technical Report 1: Moist Heat Sterilization in Autoclaves, draft 12C, 2002.
2. PDA, Technical Report 22: Process Simulation Testing for Aseptically Filled Products, 1996.
3. "‹1211› Sterilization and Sterility Assurance of Compendial Articles," in USP 29 (US Pharmacopeial Convention, Rockville, MD, 2006).
4. Decision Trees for the Selection of Sterilization Methods (CPMP/QWP/155/96), 1999.
5. Validation protocol, circa 1980.
6. Validation protocol, circa 1990.
7. FDA, 21 CFR 600.11 (b)
8. FDA 21 CFR 212, Proposed June 1, 1976, withdrawn 1991.
9. I. Pflug, Microbiology & Engineering of Sterilization Processes, 10th ed. (Environmental Sterilization Services, St. Paul, MN, 1999).
Figure 1
Figure 2
Table II: Log reduction and PNSU in selected cycles.
Table I: Definitions of overkill sterilization and assessments of the validation difficulties for each.
Figure 3
Figure 4
Figure 5
Figure 6
The author clarifies the definition and objectives of overkill sterilization for steam sterilization cycles. Current sterilization practices are reviewed and the validation difficulties associated with the various definitions of overkill sterilization are explored.
The overkill method is perhaps the most common method used in the development and validation of sterilization processes. Overkill sterilization primarily is applied to the moist-heat processing of materials, supplies, and other heat-stable goods. It generally is considered to be the simplest and most straightforward method for the design and validation of moist-heat sterilization processes. Although this is true, there is substantial confusion about how to use the overkill method and, in fact, regarding what actually constitutes an overkill process. Confusion associated with the overkill approach exists in all of the widely used sterilization technologies; that is, moist heat, dry heat, gas, and radiation. This article focuses on steam sterilization, of which there is both a greater amount of published definitions and a more precise and generally accepted understanding of the underlying science.
A contemporary definition of overkill moist-heat sterilization follows: "This is usually achieved by providing a minimum 12-log reduction of microorganisms having a D-value of at least one minute at 121 °C" (1). This is a simple-enough definition. Unfortunately, it cannot be demonstrated in a straightforward manner with presently available technology. What this definition suggests is that overkill requires a 12-D process, which equates to lethality sufficient to deliver a 12 × D 121 lethality level. This is not a lethality standard at all, however, because it inappropriately links the process lethality requirement to the characteristics of a specific biological indicator (BI). This article reviews present sterilization practices and explores the difficulties inherent in this definition.
Sterilization basics
Sterilization as a process can be rather simply defined as:
a validated process used to render a product free of viable organisms. In a sterilization process, the nature of microbiological death or reduction is described by an exponential function. Therefore, the number of microorganisms which survive a sterilization process can be expressed in terms of probability. While the probability may be reduced to a very low number, it can never be reduced to zero (2).
Figure 1
The difficulty lies in demonstrating the effectiveness of that process. The death of microorganisms by any sterilization method has been shown to generally follow a straight line termed the "death curve" (see Figure 1).
Figure 2
This phenomenon occurs with all microorganisms and is not restricted to any particular species. The slope of this line represents the resistance of the microorganism to the sterilization process. The death curve for organisms exhibiting substantial resistance will have a shallow slope, and those with low resistance to the sterilization process will have a much steeper slope (see Figure 2).
The difference in microbial resistance is critical to sterilization validation. The microbial genera Geobacilli, Bacilli, and Clostridia, having substantial resistance to the sterilization process, are commonly chosen as BIs to provide an appropriate evaluation of the process. These BI organisms are stipulated to be spore populations that have much higher resistance to sterilization processes than the vegetative cells that predominate in the normal microflora found in pharmaceutical production environments. Using these spores as indicator organisms creates a process challenge that is inherently worst-case. In the case of moist heat in which sterilization conditions are very well defined and understood, BIs are best used to establish that there is sufficient correlation between physically measured lethality, generally in the form of thermometric data, and biological lethality measured using calibrated BIs.
Sterilization processes are designed using one of three basic approaches (including the overkill method), each of which requires some degree of knowledge of the resistance and population of the bioindicator and bioburden (1). The bioburden method requires detailed knowledge and control over the bioburden resistance and population. The bioburden/biological indicator (BB/BI) method relies on the difference in resistance of the bioburden and BI (see Figure 2). With information about and control over the bioburden population and resistance, sterilization cycles requiring less time and temperature (relative to the overkill method) can be used successfully. Both of these methods allow for lower heat input to the materials being processed (an important consideration for terminal sterilization of filled product containers or the sterilization of in-process fluids and laboratory media), provided that increased attention is paid to presterilization bioburden.
The overkill method relies upon the selection of a lethality level known to be adequate to ensure sterilization without routine control over bioburden. A delivered F 0 of 12 min is an example of an overkill level of lethality. The basis for this level is that if the bioburden on an article were one million and all of that bioburden consisted of resistant spores with a D 121 value of 1 min, then a 10–6 probability of a nonsterile unit (PNSU) would be consistently attained. Obviously, this reflects worst-case assumptions regarding both the bioburden level and resistance, which would in every instance be lower in the real-world condition. The role of the BI would be to prove that there is a strong correlation between a physically determined F 0 of 12 min and biological lethality at the location of the indicator. A good correlation between biological and physical lethality ensures that an efficient and well-designed cycle with suitable steam penetration and air removal (where necessary) exists.
If understanding of overkill sterilization were all that is needed, this effort would be complete. The difficulty lies in validating overkill sterilization in a manner that is easily defendable to those unfamiliar with sterilization science and realistic in its execution. The first and simplest step is to define the minimum process objective for the sterilization process. The objective is the universal maximum probability of a single nonsterile unit (PNSU) in 106 units (a PNSU of 1 × 10–6 for any individual item). This is nothing more than an acceptable risk of contamination, whose origin (in the food industry) goes back many years. This criterion is the same for all sterilization processes, regardless of the sterilization method or the cycle approach used. The expectation is that the routine process will achieve the desired PNSU and that the routine process requirement does not apply to the validation effort. If that were not the case, then there would be no difference in the cycle approaches. The intent is always to establish the process such that it provides the same minimum confidence in the sterilized materials regardless of the varying controls defined.
Definitions of overkill cycles
Table I: Definitions of overkill sterilization and assessments of the validation difficulties for each.
The difficulties with overkill sterilization begin at this point. What is an overkill process? Including the currently prevalent definition of overkill given previously, there are various definitions, each of which satisfies the base requirement of a maximum PNSU of 1 in 10–6 but with varying process requirements. These definitions are presented in Table I, including assessments of the validation difficulties associated with each. It should be immediately evident, that the definitions are nonidentical, and thus the process required to achieve overkill is not constant for the various methods. The differences and difficulties associated with the varying definitions is a problem of some magnitude and is the main reason this article was developed.
What should be immediately evident is that the various definitions of overkill, and thus the validation of overkill sterilization for moist-heat processes, lack consistency. Simply put, demonstration of overkill is variable depending upon the regulatory or compendial expectations. Perhaps most unfortunate of all, none of the definitions include a requirement for nor provide a means to directly support a PNSU of 1 in 10–6, which is something every sterilization process is expected to achieve.
The half-cycle method
To support the minimum PNSU, some practitioners adopt the half-cycle approach in which a 106 population of a resistant indicator is inactivated during the validation effort, and then the exposure period is doubled in routine operation. It relies on simple mathematics. Killing a BI with an initial population of 106 in the half-cycle validation study means at least a 9-log reduction has been attained. (A routine sterilization cycle with double the exposure period projects to >18-log reduction). This assumes the bioburden is identical in count and resistance to the BI, which is virtually impossible in the real world. The PNSU for a typical bioburden microorganism using this approach could easily exceed 10–200 or greater (see Table II for an example of half-cycle using an 8-min validation cycle and 16-min routine cycle with an initial microbial population of 106).
Figure 3
Figure 3 represents this process and the effect on the BI microorganism. (The D 121 value of the BI in Figures 3–6 is approximately 1 min.) The slope of the death curve, which depicts the number of surviving microorganisms at a time point, is known precisely only during the survivor-curve region where the number of survivors can be readily determined. The numbers of potentially surviving BI organisms in the fraction-negative region can be estimated using various methods requiring multiple challenge units exposed at cycles where some but not all of the BIs are rendered sterile. Extension of the death curve below a survival probability of 1 × 10–2 to 1 × 10–3 assumes that the death curve is logarithmically linear. This is a reasonable assumption because microbial death follows essentially first-order kinetics.
The confirmation of a 1 × 10–6 PNSU using any microbial challenge available can only be assumed, but it can be assumed with a high degree of confidence based upon biological lethality data. This salient point must be accepted without question. Irving Pflug has explained, "Accept that while the objective of a sterilization process may be a PNSU of 10–6, we cannot directly measure microbial levels of less than one surviving microorganism in 10 to 100 units (from 10–1 to 10–2). Therefore when designing or validating sterilization processes, we use indirect methods, so we have real measurements that are equivalent to our nonmeasurable PNSU of 10–6" (9).
Figure 4
In a sterilization validation study using an initial BI population of 106 spores per indicator, 20 strips per study, and three replicate runs in which no survivors are observed, the log reduction demonstrated requires approximately 9 logs (106 × 20 × 3 = 6 × 107 reduced to zero survivors) (see Figure 4).
Figure 5
If this process is considered the half cycle, then the full cycle (with twice the exposure time) is depicted in Figure 5.
Because the lethality of the full cycle cannot be demonstrated using a biochallenge and recalling that a 106 BI challenge is destroyed in the half cycle, the log reduction delivered to the BI must be assumed. Using the assumed log reduction for the half cycle and doubling the dwell time, the log reduction for the BI in the full cycle can be estimated at 18 logs and easily meets the overkill definition of a minimum 12-log reduction of a BI with a D-value of 1 min (assuming the BI had a D 121 > 1 min) as is typical in nearly all overkill validation studies.
Figure 6
There are several inherent assumptions with the half-cycle method. The first assumption is that the bioburden would be as numerous and resistant as the BI. Second, it is assumed that the complete destruction of the multiple BIs in triplicate studies demonstrated a 9-log reduction of that BI. Finally, the death curve of the BI is assumed to be linear in a region where it cannot be experimentally determined.
Sterilization process objective
The routine sterilization of items in any sterilization process is intended to destroy the bioburden microorganisms that might be present on or in the materials being processed, regardless of their initial population and resistance. The goal is constant: to attain a minimum PNSU of 10–6. Consider the following definition of overkill sterilization as being consistent with what process expectations should be:
Overkill sterilization is a process where the destruction of a high concentration of a resistant microorganism supports the elimination of bioburden that might be present in routine processing. That objective can be demonstrated by attaining any of the following: a defined minimum F 0, a defined time-temperature condition, or a defined log reduction of a biological indicator.
This definition reflects the process requirement directly, with full recognition that bioburden organisms typically have minimal heat resistance. Destruction of the BI in high concentration requires time and temperature conditions far in excess of what is required to destroy the bioburden, and thus overkill is demonstrated.
Demonstrating a minimum PNSU of 1 × 10–6 for a sterilization process can be ensured only where the number and resistance of the microorganisms present on or in the items being sterilized is known. This can be accomplished definitively using any of the sterilization-cycle approaches described previously, and delivering that lethality is not restricted to the overkill method. It is supported by information about the relative resistance of the bioburden to the biological indicator in the BB/BI method in which partial kill of the indicator is sufficient to support the required minimum PNSU for the bioburden. With the overkill method, complete destruction of the resistant BI in high numbers is more than sufficient to ensure the minimum PNSU for any conceivable bioburden.
In everyday usage of sterilizing equipment, the BI is not present. The process is expected to confidently destroy the bioburden. In today's industry, we have numerous controls on the pre-sterilization bioburden, and in many instances, especially terminal sterilization, it is monitored for each sterilizer load.
Table II: Log reduction and PNSU in selected cycles.
If we were to make a worst-case bioburden assumption, it might be a maximum of 1000 CFU of a resistant sporeformer such as Bacillus subtilis or Bacillus atrophaeus. These mesophilic sporeformers are occasionally found in pharmaceutical plants during environmental monitoring and bioburden sampling. The maximum reported D 121 for these species is <0.5 min. It should be immediately evident from Table II that the 8-min validation (the half cycle) cycle achieves the maximum PNSU that exceeds the 1 in 10–6 expectation for any microorganism with D 121 ≤1 min. For the assumed bioburden of 0.5 min, the log reduction in the half cycle relative to a BI with D 121 = 1 min is greater than 18 logs. The half-cycle process will reproducibly attain the universal expectation of a minimum PNSU on 1 × 10–6. For bioburden organisms that are not sporeformers, the level of safety is even greater (see Table II).
Overkill sterilization is thus attained for bioburden microorganisms (even those with substantial resistance) in relatively short cycles without the need to double the cycle. The excessive heat input necessary to use a half-cycle approach should not be considered benign. Elastomeric closures, tubing, filters, gasket materials, hoses, and other materials that are commonly sterilized using the overkill method can all suffer adverse effects as a consequence of extended sterilization times. Obviously, the half-cycle approach should never be used for heat-sensitive materials, as it almost always results in unnecessary degradation of the material being processed.
Although the half-cycle method might seem acceptable to some, it strikes this author as an overly conservative approach that belies the customary industry controls on bioburden. There is little, if any, scientific rationale for its continued use in steam sterilization. Requirements for environmental monitoring, cleaning validation, bioburden monitoring, and component preparation all serve to ensure that presterilization bioburden will approach neither the population nor the resistance of the biological indicator. If resistance and count are within reasonable control—that is, being nonthermophilic and meeting the local environmental limits—then any of the alternative approaches can be used.
Conclusion
Process expectations for demonstration of a minimum PNSU of 10–6 are essentially universal. Overkill sterilization in its many variants is only one means of demonstrating that minimum expectation. Its demonstration for routine processing relies on either knowledge or assumptions regarding the bioburden number and resistance and little else. As the challenge microorganism is not present in routine sterilization, only information about the bioburden is relevant to establishment of the desired PNSU.
James Agalloco is president of Agalloco & Associates, PO Box 899, Belle Mead, NJ 08502, tel. 908.874.7558, jagalloco@aol.com [jagalloco@aol.com]
He is also a member of Pharmaceutical Technology's Editorial Advisory Board
Keywords: Sterilization
References
1. PDA, Technical Report 1: Moist Heat Sterilization in Autoclaves, draft 12C, 2002.
2. PDA, Technical Report 22: Process Simulation Testing for Aseptically Filled Products, 1996.
3. "‹1211› Sterilization and Sterility Assurance of Compendial Articles," in USP 29 (US Pharmacopeial Convention, Rockville, MD, 2006).
4. Decision Trees for the Selection of Sterilization Methods (CPMP/QWP/155/96), 1999.
5. Validation protocol, circa 1980.
6. Validation protocol, circa 1990.
7. FDA, 21 CFR 600.11 (b)
8. FDA 21 CFR 212, Proposed June 1, 1976, withdrawn 1991.
9. I. Pflug, Microbiology & Engineering of Sterilization Processes, 10th ed. (Environmental Sterilization Services, St. Paul, MN, 1999).
Figure 1
Figure 2
Table II: Log reduction and PNSU in selected cycles.
Table I: Definitions of overkill sterilization and assessments of the validation difficulties for each.
Figure 3
Figure 4
Figure 5
Figure 6
GE Healthcare — efficient facility validation
GE Healthcare's Victor Bornsztejn offers insight to help companies achieve more efficient validation, which ultimately leads to a wide range of benefits including cost containment, reduced approval times and assurance of traceability.
Q1: What are the main issues with how manufacturers are currently validating their facilities and what impact do they have?
Manufacturers must achieve regulatory compliance of facilities, laboratories and equipment more efficiently (i.e., faster, with standardized documentation, elimination of unnecessary work, reduction of errors, etc.). Current facility validation processes are based on traditional models where validation tends to start during or after facility design and ends with the handover of the facility. In our opinion, this validation effort begins too late and can lead to significant issues such as lack of transparency and standardization, and validation projects running over-budget and over-time. Many manufacturers start by putting together a very large and detailed site validation master plan (VMP) that contains a plethora of information such as:
Q2: What facility validation services do GE Healthcare offer?
We believe there is a disconnect between drug/process development, validation of facilities and ongoing facility compliance management. This is why we have launched a global service for complete facility validation for new or existing builds, including all facilities, utilities, equipment, computer systems etc.
We understand that many manufacturers work against a background of high activity with a proportional level of supporting documentation. Therefore, we have introduced a Modular Validation Platform (MPV) that allows manufacturers to benefit from the development of a workable and economic validation policy that is compliant with all current and foreseeable initiatives. It minimizes exposure of surplus information, while optimizing the level of control and ease of inspection. It also provides a springboard for future validation programmes.
Our approach is for planning to start before the facility has been designed. It involves thinking about validation holistically and not developing detailed documents too early — invariably they will need modifying and adapting as the validation programme progresses. We start putting together a modularized document/master plan that begins with the high-level detail (e.g., setting out intent and broad observations) and then building in other details as the facility design and construction progresses (Figure 1). We use automated document generation software to make the process faster and more accurate, and all validation decisions are supported by a unique regulatory database; together these provide an efficient compliance status capability with full traceability.
Q3: What benefits are provided by using your Facility Validation approach?
There are a number of advantages to the MVP compared with traditional facility validation strategies, including:
cost containment
no duplication of information
minimized impact of change
minimum exposure during inspections
timely generation of protocols
no repeat generation of test detail
optimized pre-approval of test detail
minimal discrepancies
reduced document review/approval times
proven history of acceptability
assurance of traceability to agreed user requirements.
As part of overall project management, we also apply operational excellence methodologies such as Lean and Six Sigma where appropriate.
The main point to stress here is that our approach focuses on building long-term relationships with customers through sharing our experience and expertise across the entire product and facility life cycle. This can help reduce approval times, which means facilities can go on-line earlier and products can get onto the market quicker. It also enables customers to become more self sufficient for the future. Q4: Do you believe your customers and potential customers have enough industry knowledge about facility validation?
We believe that industry knowledge is highly variable and dependent on one critical factor — resources. Validating a facility is expensive in terms of costs, personnel and time. Many people in the industry do not understand how poorly validation can be managed, and how much time and money could be saved if facility validation was effectively planned during facility design, initiated BEFORE the facility is being built and efficiently executed during and after facility construction to ensure timely completion of validation reporting and, ultimately, facility approval by regulators.
Q5: What are the main issues faced by your customers?
The biggest issue is regulatory compliance. Poorly or incorrectly validated facilities, processes and life cycles cost manufacturers millions of dollars in lost product and time. Customers are regularly receiving citations and warnings that are linked to their validation, or lack thereof, usually for reasons that can be avoided by use of a holistic validation strategy.
Q6: At which point in the life cycle do you get involved?
For new facilities, we ideally need to be involved right from the start — at least when customers are planning their new facility. We can start in an advisory capacity even before a decision has been made on a new facility, which allows an ideal risk-based approach to be built from the beginning. Otherwise, we can come in at any stage as we can also work with existing facilities that need to update/review their validation programmes.
Q7: How do you see facility validation developing in the future?
There is a lot of discussion regarding ‘risk-based’ validation and regulatory authorities are advocating the use of this type of approach. However, as an industry, we are still some way from fully realizing that. Inevitably, the industry will develop strategies to use risk-based approaches to manufacture and validation. We’re also going to see early process development become more important (e.g., improved process knowledge enabling PAT-driven processes) and more leveraging of automation to drive document generation and project management. The onus is on companies, such as ourselves, to help educate manufacturers in how to validate early and validate correctly — which can ultimately make a huge difference to their business.
www.gelifesciences.com/service
Victor.Bornsztejn@ge.com [victor.bornsztejn@ge.com]
Q1: What are the main issues with how manufacturers are currently validating their facilities and what impact do they have?
Manufacturers must achieve regulatory compliance of facilities, laboratories and equipment more efficiently (i.e., faster, with standardized documentation, elimination of unnecessary work, reduction of errors, etc.). Current facility validation processes are based on traditional models where validation tends to start during or after facility design and ends with the handover of the facility. In our opinion, this validation effort begins too late and can lead to significant issues such as lack of transparency and standardization, and validation projects running over-budget and over-time. Many manufacturers start by putting together a very large and detailed site validation master plan (VMP) that contains a plethora of information such as:
- system lists and descriptions
- impact assessments
- validation rationales
- process descriptions
- equipment, process and analytical validation.
Q2: What facility validation services do GE Healthcare offer?
We believe there is a disconnect between drug/process development, validation of facilities and ongoing facility compliance management. This is why we have launched a global service for complete facility validation for new or existing builds, including all facilities, utilities, equipment, computer systems etc.
We understand that many manufacturers work against a background of high activity with a proportional level of supporting documentation. Therefore, we have introduced a Modular Validation Platform (MPV) that allows manufacturers to benefit from the development of a workable and economic validation policy that is compliant with all current and foreseeable initiatives. It minimizes exposure of surplus information, while optimizing the level of control and ease of inspection. It also provides a springboard for future validation programmes.
Our approach is for planning to start before the facility has been designed. It involves thinking about validation holistically and not developing detailed documents too early — invariably they will need modifying and adapting as the validation programme progresses. We start putting together a modularized document/master plan that begins with the high-level detail (e.g., setting out intent and broad observations) and then building in other details as the facility design and construction progresses (Figure 1). We use automated document generation software to make the process faster and more accurate, and all validation decisions are supported by a unique regulatory database; together these provide an efficient compliance status capability with full traceability.
Q3: What benefits are provided by using your Facility Validation approach?
There are a number of advantages to the MVP compared with traditional facility validation strategies, including:
As part of overall project management, we also apply operational excellence methodologies such as Lean and Six Sigma where appropriate.
The main point to stress here is that our approach focuses on building long-term relationships with customers through sharing our experience and expertise across the entire product and facility life cycle. This can help reduce approval times, which means facilities can go on-line earlier and products can get onto the market quicker. It also enables customers to become more self sufficient for the future. Q4: Do you believe your customers and potential customers have enough industry knowledge about facility validation?
We believe that industry knowledge is highly variable and dependent on one critical factor — resources. Validating a facility is expensive in terms of costs, personnel and time. Many people in the industry do not understand how poorly validation can be managed, and how much time and money could be saved if facility validation was effectively planned during facility design, initiated BEFORE the facility is being built and efficiently executed during and after facility construction to ensure timely completion of validation reporting and, ultimately, facility approval by regulators.
Q5: What are the main issues faced by your customers?
The biggest issue is regulatory compliance. Poorly or incorrectly validated facilities, processes and life cycles cost manufacturers millions of dollars in lost product and time. Customers are regularly receiving citations and warnings that are linked to their validation, or lack thereof, usually for reasons that can be avoided by use of a holistic validation strategy.
Q6: At which point in the life cycle do you get involved?
For new facilities, we ideally need to be involved right from the start — at least when customers are planning their new facility. We can start in an advisory capacity even before a decision has been made on a new facility, which allows an ideal risk-based approach to be built from the beginning. Otherwise, we can come in at any stage as we can also work with existing facilities that need to update/review their validation programmes.
Q7: How do you see facility validation developing in the future?
There is a lot of discussion regarding ‘risk-based’ validation and regulatory authorities are advocating the use of this type of approach. However, as an industry, we are still some way from fully realizing that. Inevitably, the industry will develop strategies to use risk-based approaches to manufacture and validation. We’re also going to see early process development become more important (e.g., improved process knowledge enabling PAT-driven processes) and more leveraging of automation to drive document generation and project management. The onus is on companies, such as ourselves, to help educate manufacturers in how to validate early and validate correctly — which can ultimately make a huge difference to their business.
www.gelifesciences.com/service
Victor.Bornsztejn@ge.com [victor.bornsztejn@ge.com]
Can blow-fil-seal help deliver success?
By Andreas Graf
Reducing time to market, optimizing the use of equipment and assets, maximizing yield and reducing the costly validation process are key requirements for pharmaceutical manufacturers. When new technology emerges, such as the increasing use of blow-fill-seal delivery, providers of ancillary processes such as packaging machinery vendors can also take a role in aiding the pharma companies. This article describes how packaging vendors can play their part.
Blow-fill-seal (BFS) products are rapidly gaining ground as the preferred delivery method for many oral and ophthalmic treatments in the pharmaceutical industry. The adoption of BFS has, however, created new requirements for product packaging systems. This article examines these requirements and discusses how they can best be addressed. Key points |
Secondary packaging equipment will comprise a carton former, a top-loading platform, a tray closer and a case packer — all located at the end of the packaging line. To further reflect the reality of modern installations, the line will be configured to handle several BFS card formats as single or multiple packs, as well as various sizes of tray.
Clearly, for applications in the pharmaceutical industry, verification of printed data, such as lot numbers and expiry dates, is an essential requirement. Fortunately, this can readily be achieved in this packaging line using vision systems.
 |
In many pharmaceutical manufacturing plants, cards of BFS vials are blown, formed, filled and sealed in a process that is separate from the packaging line. Typically, the cards are made up of four or five vials containing the portioned pharmaceutical infusion liquid. After manufacture, these cards are bulk stored with random orientation.
The first stage of the packaging process is, therefore, to deload the cards by placing them on a transport conveyor that moves them to a bowl feeder; automatically stopping and starting the conveyor system can readily prevent overloading.
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When the BFS cards leave the bowl feeder, they must then be placed and stacked precisely ready for flow wrapping. The high throughput needed in today's installations means that a robot-based solution with picking rates of at least 100 products/min is virtually essential.
Let us not forget however, that the orientation of the BFS cards at this stage is still not uniform. A vision system is, therefore, needed to capture an image of each product and determine its orientation. With this information, the robot system can work at maximum efficiency and with the minimum risk of product damage. Conveniently, the same vision system can be used to verify key product parameters and initiate the rejection of any products that fail to meet the required specifications. A separate image is captured for each and every product, which means that the product profile can be accurately verified by comparing it with a stored reference shape.
A log of rejected profiles can also be maintained and the reject rate calculated in real-time. Should this rate exceed a preset value, arrangements will usually be in place to halt the operation of the machine so that the source of the problems can be determined and addressed.
The type of robot used for placing and stacking the BFS cards is important. Conventional multi-axes designs have limited flexibility, often combined with high inertia that limits operating speeds. An alternative design however, uses a structure based on jointed arms suspended below the operating mechanism. The arms meet at the gripper device, giving the robot an overall appearance somewhat similar to a spider with its legs joined at their tips.
This arrangement allows arms with low mass to be used, so it has inherently low inertia, which means that high operating speeds can be achieved with ease. It also provides the versatility needed to allow the system to handle multiple pack sizes and product stacking patterns.
Flow wrapping
BFS products are most frequently supplied in hermetically sealed packaging; making use of materials with low permeability for oxygen and water vapour and additional functions such as light protection.
Flow wrappers are readily available, but not all can provide an extended dwell time for the sealing cycle while maintaining the necessary high throughput. Extended dwell time is highly desirable, if not essential, in pharmaceutical applications with the highest requirements for sealing integrity and tightness.
Further features appropriate to the pharmaceutical industry that are provided by industry-orientated flow wrapping machines include water-cooled cover plates for the longitudinal sealing section to protect the product, and gas flushing to facilitate the use of modified and controlled atmosphere packaging. Cross-seal gusseting for multipacks is also useful, as is online verification of sealing parameters to control process reliability. Finally, in our example application, which involves the use of multiple packaging formats, a fully servo-driven machine will offer the benefit of fast, easy recipe changes.
Carton forming and filling
Flow-packed BFS products are invariably supplied in cartons. Typically, in the pharmaceutical industry, these are designed with a front flap closure that is tucked in, with dust flaps to each side. Carton forming is a relatively straightforward process, but 100% inspection is recommended to ensure that the cartons are glued perfectly every time. Facilities for inserting user information leaflets can also be provided at this stage.
Loading the flow-packed products into the cartons is another process where robots provide an optimum solution. In this case, robots of relatively conventional design can be used, but there are still a number of special features that aid productivity and flexibility.
For example, the ability of the loading system to stack the flow packs vertically or horizontally is invaluable, as is product-specific handling design to place the flow packs very tightly within the carton, thereby minimizing the size of carton needed for a particular product.
After being filled by the robot loading systems, the cartons require closing. An essential element of this process is precise carton control to ensure that the dust flaps are folded inside, before the top flap is closed and the front flap is tucked in. With most packs, no glue is required, and facilities for changing the pack size without having to change machine parts are highly desirable. In many cases, this is also a convenient stage to mark the cartons with final production data by laser coding, printing or labelling.
The final stage
The last operation to be performed by our integrated packaging line is the packing of the individual cartons into cases for shipping. A similar robot system to that used for carton filling can conveniently be used for this process, complemented by a case closer that folds the case flaps and seals them with tape.
Qualifying the system
In the pharmaceutical industry, there are clear demands for good manufacturing practice (GMP) and machine qualification procedures. Extensions to FDA regulations, including 21 CRF Part 11, have also placed greater emphasis on validation and product traceability. Purchasers of packaging lines can address all of these requirements by drawing up detailed specifications but, in some cases, there may be a faster, easier and more cost-effective approach.
This is to make full use of the application adjusted standard documentation supplied by the system vendor, adding to it only where necessary. This procedure is considerably simplified when, as suggested in this article, the whole of the packaging installation is sourced from a single supplier.
Naturally, relying on vendor documentation is only an option when the system purchaser can be totally confident that this is dependable and comprehensive.
The most enlightened suppliers to the pharmaceutical industry have addressed these issues by, for example, developing basic standard documents for functional design specification and design qualification, as well as installation qualification (IQ) and operational qualification (OQ) plans based on customer end-user requirement specifications (URS). In this process, adherence to the V-model commonly used in the pharmaceutical industry is an advantage.
Reducing time-to-market
Another development that suppliers of packaging machinery to the pharmaceutical industry have had to accept in recent years is the pressing need of their customers to bring new products to market quickly. This demand is not only addressed by shortened delivery times, but also by achieving full productivity as soon as possible after installation.
Careful design of the installation plays a significant role in this by ensuring that the system is easy to install and commission. Comprehensive pretesting and prequalification at the vendor's premises is another important element, but there is a further key factor, which is easily overlooked. This is the quality and unification of the operator interface.
A well-designed operator interface, based on modern graphical display and touchscreen technologies, greatly reduces the need for operator training and the risk of errors during the early stages of operation. Similarly, the use of a common control technology for all sections of the packaging process such as feeding, handling, flow-wrapping and secondary packaging ensures a consistent look and feel that further reduces the need for training. These are important ingredients in putting the installation to productive use in the shortest possible time.
BFS packaging creates its own special demands. Attention to detail at each stage of the packaging process, following the guidelines discussed in this article, provides a solid foundation for satisfying these demands. Overall, however, the best solution is to adopt a holistic approach to the specification, design and purchasing of the whole packaging system.
Such an approach not only guarantees that the line components will function optimally with each other, but also simplifies and speeds both commissioning and operator training. Finally, providing that a supplier is selected who is aware of and responsive to the particular needs of the pharmaceutical industry, the holistic approach can do much to reduce the cost and effort involved in meeting the industry's stringent technical requirements.
Conclusion
The economies in the system approach described are not only suitable for packing blockbuster products with high volumes involved, but are also realizable for smaller production by leveraging system and product flexibility in the engineering phase. Such an approach brings about time-to-market reductions, which is vital for both big pharma, small pharma and subcontract manufacturers. The use of packaging systems, rather than discrete standalone equipment, reduces the validation process since the vendor can share the responsibility for validating its system. Partnering with a large a reputable supplier also underwrites this approach because there is assurance of continuity of identical spare parts and again a responsibility for the entire system.
Andreas Graf is product manager pharma, medical and healthcare at Bosch Packaging, Germany.
Key points
Current Perspectives on Aseptic Formulations
By Dave Abram
The author details the factors in formulation design, requirements in facilites and equipment, and validation criteria for aseptic formualtions.
This article is part of PharmTech's supplement [http://supplement|~pharmtech.findpharma.com/pharmtech/issue/issuedetail.jsp?id=18308] "Injectable Drug Delivery."
The formulation process for parenteral, or injectable, solutions often follows the overly simplified method of combining water for injection (WFI), active pharmaceutical ingredient (API) and excipients in a formulation vessel (FV) located within a formulation room and mixing until dissolved. The formulated solution is filtered through one or two sterilizing-grade (0.22 μm) membrane filters into a sterilized receiving vessel located in a traditional cleanroom with an International Organization for Standardization (ISO) Class 5 unidirectional airflow, isolator, or restricted access barrier system (RABS) (1). Occasionally, however, the formulated product includes a component that cannot be sterilized through filtration because the act of filtration would render the final product ineffective. These nonfilterable components may be insoluble particles suspended in a solution or they could be molecules too large to pass through a filter membrane. With the exception of terminal sterilization of the formulated or filled product, devising a means to formulate the product aseptically may be the only solution to ensure product sterility. Performing aseptic formulation requires consideration of several aspects for the entire process.
In making these evaluations, the analysis in this article assumes that the facility and equipment have been qualified and approved for parenteral production under good manufacturing practices (GMPs). The analysis takes the perspective of using a traditional cleanroom for manufacturing with the understanding that these approaches can be applied to advanced systems such as isolators or RABS and tailored as necessary.
Assess the product
The first step in determining the approach for an aseptic-formulation project is to learn the characteristics and limitations of the product. This determination will help guide the formulation process. The key elements are: the total volume to be formulated because this will influence the formulation vessel size and design; and the various components of the product capable and incapable of being sterile filtered.
The type, brand, and model of sterilizing filter selected may influence the sterilization process for the filters (autoclave or sterilization-in-place [SIP]) and may also influence the formulation process. Of those components that can be sterile filtered, it must be determined whether they should be filtered in series through the same set of filters or whether separate filters are needed for some or all components. This selection may influence the sterilization process for the filters and may also influence the formulation process.
For those components that cannot be sterile filtered, it is important to understand how those will be sterilized and where such sterilization will occur (presterilized or sterilized in-house). Sterilizing the material in house could add another layer of complexity and cost to the project, depending on the characteristics of the material. Also important to know are any specific temperature conditions required for the formulation process because these conditions will influence the FV design and potential heating and cooling equipment.
Assess existing capabilities
The existing facilities and available utilities may be adequate, may need to be modified, or may need to be designed and built to support aseptic formulation project needs. A source of clean, ISO 5-compliant, unidirectional airflow is critical for making aseptic connections and performing general aseptic operations. Additionally, some aseptic connection points may require the use of horizontal laminar airflow. Making the decision requires a good understanding of the aseptic formulation process as well as the intended sterilization process.
From a utilities perspective, if the FV will be sterilized through SIP, qualified pure-steam ports and inert-gas ports will be needed in the area intended for SIP. The pure steam-system pressure should be high enough (e.g., ≥ 40 psig) to ensure that sterilization within the FV can occur at the same time as supplying other steam-consuming equipment (e.g., autoclaves, sterilizers, and lyophilizers). The inert-gas distribution system pressure will likely exceed 100 psig. Therefore, regulators will be needed to reduce the pressure for use in drying the FV following SIP.
Formulation vessel design
Table I: Fittings required.
The FV needs to be designed for its collective intended uses, which include sterilization (autoclave or SIP), preservation of sterility following the sterilization, the aseptic-formulation process, and a robust means of aseptically transferring the sterile contents of the FV to the filling machine. The product contact surfaces of the FV should be composed of electropolished 316-L stainless steel, or they should be glass-coated if the product is not compatible with stainless steel. The FV must be sized to thoroughly mix and contain the final volume of formulated product but also able to fit through door openings within the facility. The design of the FV should include load cells for weighing materials required by the formulation. Consideration should be given to aseptic connections, in-process samples, and transferring formulated product from the FV to the filling machine (via a dip tube or bottom-outlet port). The FV may need to be jacketed and rated for pressure and vacuum depending on the product and process needs (e.g., cooling during formulation and SIP). To facilitate the performance of the process steps, various fittings need to be connected to the FV (see Table I).
Table II: Components for sterilization in place.
In the event that SIP is the chosen sterilization method for the FV, the items identified in Table II should facilitate the process.
Develop the aseptic formulation process
The existing facility, utilities, equipment, and regulations establish boundaries for the chosen aseptic formulation process. In-house expertise in manufacturing, process development, and validation all factor into the success of the project. The primary goal of the aseptic formulation process is to produce a sterile product. The following guidelines improve the chances of success:
* Minimizing the number of aseptic connections.
* Designing the FV in such a way so when sterilized, that all fittings needed in the aseptic formulation process are also sterilized (e.g., filters, sampling devices and valves).
* Exposing the aseptic connection points to a constant supply of ISO 5 unidirectional airflow. Avoid having connection points near the floor or in other areas where there is turbulent airflow (i.e., bottom-outlet valves may present aseptic connection difficulties).
* Whenever the aseptic formulation process has been developed and validated, training is critical. Train multiple operators on the "how's" as well as the "why's" of the process. If the operators fail to understand the "whys," recognizing deviations and their impact during manufacturing will be difficult. It may be helpful to include these operators in the validation activities.
* Leveraging, whenever possible, existing processes and validations.
* Although not directly related to sterility assurance, one also must put into place a filter integrity-testing strategy. Filter and immediately remove the filters to be postuse integrity-tested before proceeding; filter and proceed with the remainder of the formulation before integrity-test results are known or redundantly filtered using a series of two filters. Table III outlines advantages and disadvantages of the options.
Table III: Options in filter integrity testing.
Formulation-vessel sterilization
The sterilization method for the FV must be decided upon and the process developed. Preservation of sterility following the cycle is equally critical as the act of sterilization. Common sterilization methods that could be employed are autoclave sterilization and SIP. If the FV can fit inside the autoclave, this is the simplest option. If the FV is too large for autoclave sterilization, SIP using steam from the plant's pure-steam system will fulfill the need. SIP is more difficult than autoclave sterilization, and it presents some hazards for operators. SIP will generate substantial humidity in the area where it is being performed. This moisture presents slip–and–fall hazards, and the heat of the external surfaces of the FV can scald.
Regardless of the method chosen, the sterilization cycle needs to be developed for the FV. If autoclave sterilization will be used, the same cycle used to sterilize durable goods may be the most reasonable starting point for FV sterilization. It is suggested to place hydrophobic vent filters on the ports to be used for aseptic connections to facilitate air removal and steam penetration as well as preserving sterility following the autoclave cycle. If vent filters are not used, these connection points will be dead legs, which make air removal and steam penetration more difficult and sterilization less efficient.
If SIP will be used, cycle development will be more involved. The FV needs to be on-hand with all fittings and any other necessary equipment. Having a good idea of the general aseptic formulation process and the connections to be made will help to set the fittings on the FV as well as determine inlet and outlet points. The use of temperature measurement tools (i.e., thermocouples or data loggers) is necessary for the development of the SIP cycle. It is assumed that the SIP will be performed in a lower classified area and the sterile FV ultimately moved into an ISO 5-compliant cleanroom for the aseptic formulation.
The flow of steam through the system needs to be set up to ensure steam penetration and contact with all interior surfaces and product pathways throughout the FV and fittings. Dead legs should be avoided because air can become trapped, thereby reducing sterilization efficiency. When the SIP cycle starts, the steam will condense on the cold interior surfaces of the FV and exit through the outlet ports as water. Once the FV surfaces heat up, the condensate will gradually turn to steam. The inlet and outlet valves need to be adjusted to build the desired internal pressure to achieve sterilization. The valves to the jacket should be opened to prevent the buildup of pressure caused by the temperature increase within the vessel. After the steaming portion is complete, the FV will need to be cooled and dried with a sterile-filtered inert gas. The transition from steam to inert gas should be made gradually while maintaining positive pressure within the FV.
Following the cooling and drying cycle, preservation of sterility is critical. The manner in which sterility is preserved depends on the method of sterilization. If the FV is autoclave sterilized, it will be dried but still quite warm following the cycle. Removing the FV from the autoclave should happen under the protection of unidirectional airflow. Check all clamps for tightness while the FV is still warm. Once the FV cools to room temperature, it can be removed from the unidirectional airflow and stored in lower classification environment until use. The exterior should be sanitized before aseptic formulation begins.
If the FV is SIP sterilized, the following two options exist for preserving sterility:
* Pressurize the FV with sterile-filtered inert gas following the cool-and-dry cycle. All outlet valves will be closed, first the outermost outlet valves and last the inlet valve. All clamps should be tightened. The exterior of the pressurized FV will be sanitized (sanitization method should be qualified). The sanitized FV will be moved into an ISO 5 environment until use. The FV could remain in lower classified environments provided that the internal pressure is maintained until use. If the internal pressure is lost before being placed in an ISO 5 environment, contamination concerns will need to be addressed.
* Pressurize the FV with sterile-filtered inert gas following the cool–and–dry cycle and perform an integrity test of the FV with all fittings. This integrity test will involve closing the valves and measuring the pressure decay as a result of cooling. If the FV has leaks, the pressure loss will be greater than the pressure loss due to cooling alone. Once passing results are obtained, the FV could be stored in a lower classified environment until needed for use. The exterior would still need to be sanitized.
Performance qualification of FV sterilization
Regardless of the method selected for sterilizing the FV, performance qualification (PQ) must be performed. If autoclave sterilization was the chosen method, the PQ of the cycle will follow the same process that has been used for other durable loads. If SIP was the chosen method, there are two basic parts of the SIP cycle to consider: sterilization and drying. To qualify the sterilization portion, the FV will need to be assembled as in manufacturing and probed with thermocouples, data loggers, and biological indicators (BI). The placement of the thermocouples and BIs should be in locations thought to represent the worst-case areas regarding steam penetration. The SIP cycle should be run at worst-case parameters when compared to those used for routine manufacturing. For example, if the parameters used for manufacturing are anticipated to be 30 min at a steam pressure of ≥ 18 psig, the parameters used for the PQ should use a shorter timeframe and lower pressure to provide additional sterility assurance. One method for controlling the pressure during the cycle at a specific pressure is to replace the outer diaphragm valve with a needle valve, allowing for more precise control of steam flow.
Following the steam portion of the SIP cycle, the FV should be dried using sterile filtered inert gas. Following the drying portion, the FV will need to be closed in a manner to retain positive pressure and preserve sterility. If the strategy for manufacturing is to simply pressurize the FV and transport into the ISO 5 cleanroom, this aspect is low risk and does not need to be qualified. If the strategy is to perform a pressure hold test on the FV and relieve the internal pressure after passing results have been achieved, those success criteria need to be derived from qualification. Perform the SIP as in manufacturing (higher pressure and longer timeframe). The additional temperature and time will raise the temperature of the FV beyond that found using the sterilization-qualification parameters, which will impact the pressure loss behavior as it cools. Once the FV has been dried and cooled, close all valves to retain a positive internal pressure. Allow the FV to remain undisturbed for a short timeframe and then record the internal chamber pressure. Allow the FV to continue cooling for several hours until it reaches room temperature. Record the internal pressure and ensure that the FV indeed has retained pressure. The pressure decay as a result of cooling will be the parameters used for integrity testing during routine batch manufacture.
Validation of the aseptic formulation process
The process developed for aseptically formulating the product requires validation. The method for this process validation is the process simulation (i.e., media challenge). Running a process simulation for the recently developed aseptic formulation process uses the same basic concept as used for the aseptic-filling process simulations.
The process simulation should be performed per written batch record using the same manufacturing personnel, equipment, and facilities that will be involved in the manufacture of the actual product. Where the manufacturing process uses inert gases, these will be substituted with oil-free compressed air to promote microbial growth in the event contamination occurs. A total of three batches will be performed in which each step of the proposed manufacturing process will be included with media substituting for the product. Upon completion of the process simulation, the entire FV can be closed and incubated or a portion can be transferred as it will be performed in routine batch manufacture and that portion incubated. The media vessels should be sealed to prevent contamination from occurring during incubation.
Assessing worst cases in process simulations is a balancing act of weighing the benefits of success against the risks and consequences of failure. Building flexibility into the process, covering worst-case and some nonroutine interventions to allow the manufacturing to operate within a larger design space is desirable. This objective can only be achieved by including these worst-case scenarios and interventions in successful media challenges. In the event the media challenge fails, time and effort will be lost on the media challenge in addition to the time and effort required of an investigation. If multiple interventions were included in a failed process simulation batch, identifying the root cause of the contamination will be challenging.
Conclusion
Drug products that require aseptic formulation can present challenges. These challenges can be overcome with experienced personnel and a good understanding of the project objectives, regulatory requirements, facilities and equipment. Once the processes have been developed and validated and personnel training completed, manufacturing the aseptically formulated product will be able to proceed with relative ease.
Dave Abram is manager of validation and technical services at BioConvergence LLC, 4320 West Zenith Drive, Bloomington, IN 47404, tel. 812.961.1700, fax 812.961.1733, dave.abram@bioc.us [dave.abram@bioc.us]
Reference
1. ISO 14644-1, Cleanrooms and Associated Controlled Environments—Part 1: Classification of Air Cleanliness, First Edition, Sec. 2.4, p. 3, May 1, 1999.
Table I: Fittings required.
Table II: Components for sterilization in place.
Table III: Options in filter integrity testing.
The author details the factors in formulation design, requirements in facilites and equipment, and validation criteria for aseptic formualtions.
This article is part of PharmTech's supplement [http://supplement|~pharmtech.findpharma.com/pharmtech/issue/issuedetail.jsp?id=18308] "Injectable Drug Delivery."
The formulation process for parenteral, or injectable, solutions often follows the overly simplified method of combining water for injection (WFI), active pharmaceutical ingredient (API) and excipients in a formulation vessel (FV) located within a formulation room and mixing until dissolved. The formulated solution is filtered through one or two sterilizing-grade (0.22 μm) membrane filters into a sterilized receiving vessel located in a traditional cleanroom with an International Organization for Standardization (ISO) Class 5 unidirectional airflow, isolator, or restricted access barrier system (RABS) (1). Occasionally, however, the formulated product includes a component that cannot be sterilized through filtration because the act of filtration would render the final product ineffective. These nonfilterable components may be insoluble particles suspended in a solution or they could be molecules too large to pass through a filter membrane. With the exception of terminal sterilization of the formulated or filled product, devising a means to formulate the product aseptically may be the only solution to ensure product sterility. Performing aseptic formulation requires consideration of several aspects for the entire process.
In making these evaluations, the analysis in this article assumes that the facility and equipment have been qualified and approved for parenteral production under good manufacturing practices (GMPs). The analysis takes the perspective of using a traditional cleanroom for manufacturing with the understanding that these approaches can be applied to advanced systems such as isolators or RABS and tailored as necessary.
Assess the product
The first step in determining the approach for an aseptic-formulation project is to learn the characteristics and limitations of the product. This determination will help guide the formulation process. The key elements are: the total volume to be formulated because this will influence the formulation vessel size and design; and the various components of the product capable and incapable of being sterile filtered.
The type, brand, and model of sterilizing filter selected may influence the sterilization process for the filters (autoclave or sterilization-in-place [SIP]) and may also influence the formulation process. Of those components that can be sterile filtered, it must be determined whether they should be filtered in series through the same set of filters or whether separate filters are needed for some or all components. This selection may influence the sterilization process for the filters and may also influence the formulation process.
For those components that cannot be sterile filtered, it is important to understand how those will be sterilized and where such sterilization will occur (presterilized or sterilized in-house). Sterilizing the material in house could add another layer of complexity and cost to the project, depending on the characteristics of the material. Also important to know are any specific temperature conditions required for the formulation process because these conditions will influence the FV design and potential heating and cooling equipment.
Assess existing capabilities
The existing facilities and available utilities may be adequate, may need to be modified, or may need to be designed and built to support aseptic formulation project needs. A source of clean, ISO 5-compliant, unidirectional airflow is critical for making aseptic connections and performing general aseptic operations. Additionally, some aseptic connection points may require the use of horizontal laminar airflow. Making the decision requires a good understanding of the aseptic formulation process as well as the intended sterilization process.
From a utilities perspective, if the FV will be sterilized through SIP, qualified pure-steam ports and inert-gas ports will be needed in the area intended for SIP. The pure steam-system pressure should be high enough (e.g., ≥ 40 psig) to ensure that sterilization within the FV can occur at the same time as supplying other steam-consuming equipment (e.g., autoclaves, sterilizers, and lyophilizers). The inert-gas distribution system pressure will likely exceed 100 psig. Therefore, regulators will be needed to reduce the pressure for use in drying the FV following SIP.
Formulation vessel design
Table I: Fittings required.
The FV needs to be designed for its collective intended uses, which include sterilization (autoclave or SIP), preservation of sterility following the sterilization, the aseptic-formulation process, and a robust means of aseptically transferring the sterile contents of the FV to the filling machine. The product contact surfaces of the FV should be composed of electropolished 316-L stainless steel, or they should be glass-coated if the product is not compatible with stainless steel. The FV must be sized to thoroughly mix and contain the final volume of formulated product but also able to fit through door openings within the facility. The design of the FV should include load cells for weighing materials required by the formulation. Consideration should be given to aseptic connections, in-process samples, and transferring formulated product from the FV to the filling machine (via a dip tube or bottom-outlet port). The FV may need to be jacketed and rated for pressure and vacuum depending on the product and process needs (e.g., cooling during formulation and SIP). To facilitate the performance of the process steps, various fittings need to be connected to the FV (see Table I).
Table II: Components for sterilization in place.
In the event that SIP is the chosen sterilization method for the FV, the items identified in Table II should facilitate the process.
Develop the aseptic formulation process
The existing facility, utilities, equipment, and regulations establish boundaries for the chosen aseptic formulation process. In-house expertise in manufacturing, process development, and validation all factor into the success of the project. The primary goal of the aseptic formulation process is to produce a sterile product. The following guidelines improve the chances of success:
* Minimizing the number of aseptic connections.
* Designing the FV in such a way so when sterilized, that all fittings needed in the aseptic formulation process are also sterilized (e.g., filters, sampling devices and valves).
* Exposing the aseptic connection points to a constant supply of ISO 5 unidirectional airflow. Avoid having connection points near the floor or in other areas where there is turbulent airflow (i.e., bottom-outlet valves may present aseptic connection difficulties).
* Whenever the aseptic formulation process has been developed and validated, training is critical. Train multiple operators on the "how's" as well as the "why's" of the process. If the operators fail to understand the "whys," recognizing deviations and their impact during manufacturing will be difficult. It may be helpful to include these operators in the validation activities.
* Leveraging, whenever possible, existing processes and validations.
* Although not directly related to sterility assurance, one also must put into place a filter integrity-testing strategy. Filter and immediately remove the filters to be postuse integrity-tested before proceeding; filter and proceed with the remainder of the formulation before integrity-test results are known or redundantly filtered using a series of two filters. Table III outlines advantages and disadvantages of the options.
Table III: Options in filter integrity testing.
Formulation-vessel sterilization
The sterilization method for the FV must be decided upon and the process developed. Preservation of sterility following the cycle is equally critical as the act of sterilization. Common sterilization methods that could be employed are autoclave sterilization and SIP. If the FV can fit inside the autoclave, this is the simplest option. If the FV is too large for autoclave sterilization, SIP using steam from the plant's pure-steam system will fulfill the need. SIP is more difficult than autoclave sterilization, and it presents some hazards for operators. SIP will generate substantial humidity in the area where it is being performed. This moisture presents slip–and–fall hazards, and the heat of the external surfaces of the FV can scald.
Regardless of the method chosen, the sterilization cycle needs to be developed for the FV. If autoclave sterilization will be used, the same cycle used to sterilize durable goods may be the most reasonable starting point for FV sterilization. It is suggested to place hydrophobic vent filters on the ports to be used for aseptic connections to facilitate air removal and steam penetration as well as preserving sterility following the autoclave cycle. If vent filters are not used, these connection points will be dead legs, which make air removal and steam penetration more difficult and sterilization less efficient.
If SIP will be used, cycle development will be more involved. The FV needs to be on-hand with all fittings and any other necessary equipment. Having a good idea of the general aseptic formulation process and the connections to be made will help to set the fittings on the FV as well as determine inlet and outlet points. The use of temperature measurement tools (i.e., thermocouples or data loggers) is necessary for the development of the SIP cycle. It is assumed that the SIP will be performed in a lower classified area and the sterile FV ultimately moved into an ISO 5-compliant cleanroom for the aseptic formulation.
The flow of steam through the system needs to be set up to ensure steam penetration and contact with all interior surfaces and product pathways throughout the FV and fittings. Dead legs should be avoided because air can become trapped, thereby reducing sterilization efficiency. When the SIP cycle starts, the steam will condense on the cold interior surfaces of the FV and exit through the outlet ports as water. Once the FV surfaces heat up, the condensate will gradually turn to steam. The inlet and outlet valves need to be adjusted to build the desired internal pressure to achieve sterilization. The valves to the jacket should be opened to prevent the buildup of pressure caused by the temperature increase within the vessel. After the steaming portion is complete, the FV will need to be cooled and dried with a sterile-filtered inert gas. The transition from steam to inert gas should be made gradually while maintaining positive pressure within the FV.
Following the cooling and drying cycle, preservation of sterility is critical. The manner in which sterility is preserved depends on the method of sterilization. If the FV is autoclave sterilized, it will be dried but still quite warm following the cycle. Removing the FV from the autoclave should happen under the protection of unidirectional airflow. Check all clamps for tightness while the FV is still warm. Once the FV cools to room temperature, it can be removed from the unidirectional airflow and stored in lower classification environment until use. The exterior should be sanitized before aseptic formulation begins.
If the FV is SIP sterilized, the following two options exist for preserving sterility:
* Pressurize the FV with sterile-filtered inert gas following the cool-and-dry cycle. All outlet valves will be closed, first the outermost outlet valves and last the inlet valve. All clamps should be tightened. The exterior of the pressurized FV will be sanitized (sanitization method should be qualified). The sanitized FV will be moved into an ISO 5 environment until use. The FV could remain in lower classified environments provided that the internal pressure is maintained until use. If the internal pressure is lost before being placed in an ISO 5 environment, contamination concerns will need to be addressed.
* Pressurize the FV with sterile-filtered inert gas following the cool–and–dry cycle and perform an integrity test of the FV with all fittings. This integrity test will involve closing the valves and measuring the pressure decay as a result of cooling. If the FV has leaks, the pressure loss will be greater than the pressure loss due to cooling alone. Once passing results are obtained, the FV could be stored in a lower classified environment until needed for use. The exterior would still need to be sanitized.
Performance qualification of FV sterilization
Regardless of the method selected for sterilizing the FV, performance qualification (PQ) must be performed. If autoclave sterilization was the chosen method, the PQ of the cycle will follow the same process that has been used for other durable loads. If SIP was the chosen method, there are two basic parts of the SIP cycle to consider: sterilization and drying. To qualify the sterilization portion, the FV will need to be assembled as in manufacturing and probed with thermocouples, data loggers, and biological indicators (BI). The placement of the thermocouples and BIs should be in locations thought to represent the worst-case areas regarding steam penetration. The SIP cycle should be run at worst-case parameters when compared to those used for routine manufacturing. For example, if the parameters used for manufacturing are anticipated to be 30 min at a steam pressure of ≥ 18 psig, the parameters used for the PQ should use a shorter timeframe and lower pressure to provide additional sterility assurance. One method for controlling the pressure during the cycle at a specific pressure is to replace the outer diaphragm valve with a needle valve, allowing for more precise control of steam flow.
Following the steam portion of the SIP cycle, the FV should be dried using sterile filtered inert gas. Following the drying portion, the FV will need to be closed in a manner to retain positive pressure and preserve sterility. If the strategy for manufacturing is to simply pressurize the FV and transport into the ISO 5 cleanroom, this aspect is low risk and does not need to be qualified. If the strategy is to perform a pressure hold test on the FV and relieve the internal pressure after passing results have been achieved, those success criteria need to be derived from qualification. Perform the SIP as in manufacturing (higher pressure and longer timeframe). The additional temperature and time will raise the temperature of the FV beyond that found using the sterilization-qualification parameters, which will impact the pressure loss behavior as it cools. Once the FV has been dried and cooled, close all valves to retain a positive internal pressure. Allow the FV to remain undisturbed for a short timeframe and then record the internal chamber pressure. Allow the FV to continue cooling for several hours until it reaches room temperature. Record the internal pressure and ensure that the FV indeed has retained pressure. The pressure decay as a result of cooling will be the parameters used for integrity testing during routine batch manufacture.
Validation of the aseptic formulation process
The process developed for aseptically formulating the product requires validation. The method for this process validation is the process simulation (i.e., media challenge). Running a process simulation for the recently developed aseptic formulation process uses the same basic concept as used for the aseptic-filling process simulations.
The process simulation should be performed per written batch record using the same manufacturing personnel, equipment, and facilities that will be involved in the manufacture of the actual product. Where the manufacturing process uses inert gases, these will be substituted with oil-free compressed air to promote microbial growth in the event contamination occurs. A total of three batches will be performed in which each step of the proposed manufacturing process will be included with media substituting for the product. Upon completion of the process simulation, the entire FV can be closed and incubated or a portion can be transferred as it will be performed in routine batch manufacture and that portion incubated. The media vessels should be sealed to prevent contamination from occurring during incubation.
Assessing worst cases in process simulations is a balancing act of weighing the benefits of success against the risks and consequences of failure. Building flexibility into the process, covering worst-case and some nonroutine interventions to allow the manufacturing to operate within a larger design space is desirable. This objective can only be achieved by including these worst-case scenarios and interventions in successful media challenges. In the event the media challenge fails, time and effort will be lost on the media challenge in addition to the time and effort required of an investigation. If multiple interventions were included in a failed process simulation batch, identifying the root cause of the contamination will be challenging.
Conclusion
Drug products that require aseptic formulation can present challenges. These challenges can be overcome with experienced personnel and a good understanding of the project objectives, regulatory requirements, facilities and equipment. Once the processes have been developed and validated and personnel training completed, manufacturing the aseptically formulated product will be able to proceed with relative ease.
Dave Abram is manager of validation and technical services at BioConvergence LLC, 4320 West Zenith Drive, Bloomington, IN 47404, tel. 812.961.1700, fax 812.961.1733, dave.abram@bioc.us [dave.abram@bioc.us]
Reference
1. ISO 14644-1, Cleanrooms and Associated Controlled Environments—Part 1: Classification of Air Cleanliness, First Edition, Sec. 2.4, p. 3, May 1, 1999.
Table I: Fittings required.
Table II: Components for sterilization in place.
Table III: Options in filter integrity testing.
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