PQRI Aseptic Processing Working Group -Final Report

PQRI

Aseptic Processing Working Group

-Final Report-

Aseptic Processing Work Group -Final Report-

The PQRI Aseptic Processing Working Group has completed their work in accordance with the December 23rd, 2002 approved work plan. The working group completed its activities on March 10, 2003, 110 days from the date of it’s formation. The working group, comprised of 41 members, did an outstanding job of focusing on the specified topics and goals set forth in the work plan.

Not all areas of the FDA’s concept paper “Sterile Drug Products Produced by Aseptic Processing” were discussed in this activity, but rather several specific areas that where identified as needing additional scientific input.

As part of the work plan an industry survey was conducted to gather specific information regarding aseptic filling practices. The responses from over 45 aseptic filling sites were received and collated for use by the team. Since that date several additional surveys have been received. The complete survey results, including the additional surveys received, will be submitted for publication in the near future.

The 8 clarifications and 10 recommendation developed by the working group are presented in this document and were developed based on the expert knowledge of the work group members, survey results, and publications where applicable.

As Chairman of the Aseptic Processing Working Group, I would like to recognize, on behalf of PQRI, the outstanding dedication and contributions made by each one of the FDA, Industry, and Academia working group members. In addition, I would like to recognize and thank the working group members from the DMPQ in Office of Compliance at FDA, for their willingness to bring this topic into the PQRI framework and for their efforts to make this activity a success.

Glenn E. Wright Chairman PQRI Aseptic Processing Work Group

Page 2 of 31 March 13,2003

Aseptic Processing Work Group -Final Report-

TABLE OF CONTENTS

WORK PLAN 4

CLARIFICATIONS 10

RECOMMENDATIONS 14

Page 3 of 31 March 13,2003

Aseptic Processing Work Group -Final Report-

PQRI

Aseptic Processing Working Group

Work Plan (Approved by the PQRI Steering Committee December 23, 2002)

Page 4 of 31 March 13,2003

Aseptic Processing Work Group -Final Report-

Aseptic Processing Working Group Work Plan (Approved December 23, 2002)

Overview:

The PQRI Aseptic Processing working group will cover a defined list of points. The composition of the group will be made up of experts form the FDA, industry, and academia. The points to be covered have been divided into two categories: points for with recommendations will be made and points for which clarification comments will be made.

Working Group Members (updated):

Mr. James P. Agalloco Nigel Halls, Ph.D. Mr. Rainer F. Newman Agalloco & Associates GlaxoSmith Kline (ret.) Johnson & Johnson

James E. Akers, Ph.D. Mr. Karl L. Hofmann Ms. Jean I. Olsen Akers Kennedy & Associates Brystol-Myers Squibb Co. GlaxoSmithKline

Ms. Diane Alexander David Hussong, Ph.D. Ms. Carolyn Renshaw FDA FDA FDA

Barbara Bassler, Ph.D. Mr. Richard M. Johnson Mr. Robert Sausville Bridge Associates International Abbott Laboratories FDA

Mr. Martyn Becker Kunio Kawamura, Ph.D. Neal J. Sweeney, Ph.D. Merck & Co. Otsuka Pharma. Co., Ltd. FDA

Ms. Susan Bruederle Lee E. Kirsch, Ph.D. Mr. Ian Symonds FDA University of Iowa GlaxoSmithKline

Don G. Burstyn, Ph.D. Ms. Carol M. Lampe Laura A. Thoma, Ph.D. Alkermes Baxter Healthcare Corporation University of Tennessee

Roger Dabbah, Ph.D. Mr. Joseph Lasich Ms. Debbie Trout USP Alcon Laboratories, Inc. FDA

Mr. Roger Deschenes John Lindsay, S.M. (NRM) Brenda Uratani, Ph.D. Astra Zeneca Aseptic Solutions Inc. FDA

Mr. Joseph C. Famulare Mr. Russell E. Madsen Mr. Martin Van Trieste FDA PDA Abbott Laboratories

William R. Frieben, Ph.D. Leonard Mestrandrea, Ph.D. Richard T. Wood, Ph.D. Pharmacia Corporation Pfizer Inc. Pfizer, Inc.

Mr. Richard L. Friedman Mr. Karl Andrew Minor Mr. Glenn E. Wright FDA Eli Lilly & Co. Eli Lilly & Co.

Mr. John Grazal Kenneth Muhvich, Ph.D. Jeff Yuen, MPH, MBA AstraZeneca Pharmaceuticals Micro-Reliance. Jeff Yuen and Associates

Klaus Haberer, Ph.D. Mr. Terry E. Munson Compliance Advice & Services KMI/PAREXEL, Inc.

Page 5 of 31 March 13,2003

Aseptic Processing Work Group -Final Report-

Process:

The working group will work on the 10 recommendations and 8 clarifications as a single group. A project kickoff meeting will be held the first week in January. Members will be required to attend one 90-minute conference call each week.

Listed below are the working groups deliverables and the processes to be used. Included in the deliverables is the industry survey.

• Clarifications Clarifications on 8 specific topics are to be worked on by the working group. Topic leaders will be chosen from the PQRI working group for each point. Suggested redline clarifications are to be made by the working group and sent to the topic leader. This activity is to begin in early January. The topic leader will collect and collate the suggested clarifications and develop a redline strikeout version of the text that incorporates the various suggestions. The topic leader will lead discussions on the clarifications and make the modifications needed. A final clarification will be developed and approved by the working group. st The redline clarifications are to be completed by January 31 and sent to the PQRI steering committee for approval.

• Survey An industry survey will be performed to collect current industry information. The survey will be a data collection type of survey designed to provide information on the industries current practices. The target date to receive completed surveys will be January 20th. The surveys will be blinded by PQRI and data tabulated. The tabulated data will be provided to the work group on February 4th.

• Recommendations Recommendations on 10 specific topics are to be worked on by the working group. Discussions relating to environmental monitoring and sterilization options will be lead by Carol Lampe while the discussion on process simulation and aseptic processing isolators will be led by Richard Johnson. Discussions are targeted to begin the first week in February. The recommendations are to include the question being asked, the recommendation being provided and a brief rational section that provides information on how the recommendation was reached. A final recommendation will be approved by the working group. The recommendations must be completed by February 28th and sent to the PQRI steering committee for approval.

Timeline:

• Week of December 16th - Work Plan and Survey sent to Steering Committee for approval. • Week of December 23rd - Survey sent to companies. • First week in January - Work group begins work on clarifications. • January 20th - Surveys due to PQRI. • January 31st - Clarification work completed and sent to Steering Committee for Approval.

Page 6 of 31 March 13,2003

Aseptic Processing Work Group -Final Report-

• February 4th - Survey results compiled and provided to work group. • First week in February - Work Group begins work on recommendations. • February 28th - Work group completes recommendations and sends the recommendations to PQRI Steering Committee for approval.

Clarifications:

The PQRI working group will develop suggested clarifications for the following 8 points. The clarifications will be presented in the form of redlined revisions to the current text.

1.) Concept Paper Line Number Reference: 637

Subsequently, routine semi-annual revalidation runs should be conducted for each shift and processing line to evaluate the state of control of the aseptic process.

Clarification: What clarification should be provided in regards to each shift to help the reader understand that the process simulation needs to represent the various shifts but that a separate media fills for each shift may not be required.

2.) Concept Paper Line Number Reference: 984

Written procedures should include a list of locations to be sampled. Sample timing, frequency, and location should be carefully selected based upon its relationship to the operation performed. Samples should be taken throughout the aseptic processing facility (e.g., aseptic corridors; gowning rooms) using appropriate, scientifically sound sampling procedures, standards, and test limits.

Clarification: What clarification should be provided for the term “test limit” so that it is not confused with a specification?

3.) Concept Paper Line Number Reference: 1047

Upon preparation, disinfectants should be rendered sterile, and used for a limited time, as specified by written procedures. Disinfectants should retain efficacy against the normal microbial flora and be effective against spore-forming microorganisms. Many common sanitizers are ineffective against spores, for example,70%isopropyl alcohol is not effective against Bacillus,spp .spores. A sporicidal agent should be used regularly to prevent contamination of the manufacturing environment with otherwise difficult to eradicate spore forming bacteria or fungi.

Clarification: What clarification should be suggested regarding a disninfectants efficacy against spore forming microorganisms?

4.) Concept Paper Line Number Reference: 1055

After the initial assessment of sanitization procedures, ongoing sanitization efficacy should be frequently monitored through specific provisions in the environmental monitoring program, with a defined course of action in the event samples are found to exceed limits.

Clarification: What type of clarification should be made in regards to expectations surrounding sanitization efficacy being monitored by the environmental program?

5.) Concept Paper Line Number Reference: 1070

b. Active Air Monitoring-

Page 7 of 31 March 13,2003

Aseptic Processing Work Group -Final Report-

Manufacturers should be aware of a device's air monitoring capabilities, and should determine suitability of any new or current devices with respect to sensitivity and limit of quantification.

Clarification: What type of clarification should be made in regards to determining the suitability of new or current devices and the comment around sensitivity and limit of quantification?

6.) Concept Paper Line Number Reference: 1419

Properly operated RTPs (rapid transfer ports) are also generally considered to be an effective transfer mechanism. The number of transfers should be kept to a minimum because the risk of ingress of contaminants increases with each successive material transfer.

Clarification: What clarification should be suggested regarding the number of RTP transfers and the risk of contamination?

7.) Concept Paper Line Number Reference: 1033

In addition to microbial counts beyond alert and action limits, the presence of any atypical microorganisms in the cleanroom environment should be investigated, with any appropriate corrective action promptly investigated.

Clarification: What clarification should be suggested regarding the expectation concerning the “typical microflora”, and the definition for an atypical microorganism?

8.) Concept Paper Line Number Reference: 981

Evaluating the quality of air and surfaces in the cleanroom environment should start with a well-defined written program and validated methods. The monitoring program should cover all production shifts and include air, floors, walls, and equipment surfaces, including the critical surfaces in contact with product and container/closures.

Clarification: What clarification should be made regarding the validation of the environmental monitoring methods?

Recommendations:

The PQRI working group will develop recommendations using data from the industry survey as well as good scientific principals for the following 10 points (questions). The recommendation format will follow the example given in the Attachment.

Process Simulations

1.) Concept Paper Line Number Reference: 661

Questions: What is an appropriate number of units to be filled during a process simulation (media fill)?

2.) Concept Paper Line Number Reference: 730

Question: What is an acceptable temperature range for the incubation of media fill units using TSB and FTM? If alternative practices are used what type of justification is required?

3.) Concept Paper Line Number Reference: 787

Question: What is an appropriate limit for the contamination rate in a process simulation (media fill)? What is an appropriate target for contaminated units in a process simulation (media fill)?

Page 8 of 31 March 13,2003

Aseptic Processing Work Group -Final Report-

Environmental Monitoring

4.) Concept Paper Line Number Reference: 981

Question: When should critical surfaces be monitored? What are appropriate expectations in regards to results obtained?

5.) Concept Paper Reference Line Number Reference: 1014:

Question: What data should be considered when establishing monitoring limits? What is an appropriate frequency for re-evaluating monitoring limits?

6.) Concept Paper Line Number Reference: 82

TABLE 1- Air Classificationa

Clean Area >0.5 um >0.5 um Microbial Limitb Classification particles/ft3 particles/m3 cfu/10 ft3 cfu/m3 100 100 3,500 <1c <3c 1000 1000 35,000 <2 <7 10,000 10,000 350,000 <5 <18 100,000 100,000 3,500,000 <25 <88

a - All classifications based on data measured in the vicinity of exposed articles during periods of activity. b- Alternate microbiological standards may be established where justified by the nature of the operation. c- Samples from class 100 environments should normally yield no microbiological contaminants.

Question: What is the maximum number of viable organisms allowed in air samples for the various classifications?

Aseptic Processing Isolators

7.) Concept Paper Line Number Reference: 1369

Question: What type of airflow is required in closed isolators?

8.) Concept Paper Line Number Reference:1372

Question: What is the appropriate requirement for air handling systems in isolators?

9.) Concept Paper Line Number Reference: 1448

Question: What are appropriate methods for use in the development of decontamination cycles?

Sterilization Options

10) Concept Paper Line Number Reference: 57

Question: With respect to terminal sterilization and adjunct processing what flowcharts represent the most risk-based and scientifically developed approach?

Page 9 of 31 March 13,2003

Aseptic Processing Work Group -Final Report-

PQRI

Aseptic Processing Working Group

Clarifications

-Report- (Approved by the PQRI Steering Committee February 5th, 2003)

Page 10 of 31 March 13,2003

Aseptic Processing Work Group -Final Report-

The PQRI Aseptic Processing Working group has completed the Clarification section of its approved Work Plan. As detailed in the Work Plan, clarifications have been developed for specific passages of text identified in the FDA’s concept paper “Sterile Drug Products Produced by Aseptic Processing” published in September of 2002.

The following clarifications are being recommended by the PQRI Working Group:

• Clarification #1

Concept Paper Line Number Reference: 637

Original Text

“Subsequently, routine semi-annual revalidation runs should be conducted for each shift and processing line to evaluate the state of control of the aseptic process.”

Clarified Text

Subsequently, routine semi-annual revalidation should be conducted for each processing line to evaluate the state of control of the aseptic process. Activities and interventions representative of each shift and shift change over should be incorporated into the design of the semi-annual revalidation.

• Clarification #2

Concept paper Line Number Reference: 984

Original Text

“Written procedures should include a list of locations to be sampled. Sample timing, frequency, and location should be carefully selected based upon its relationship to the operation performed. Samples should be taken throughout the aseptic processing facility (e.g., aseptic corridors; gowning rooms) using appropriate, scientifically sound sampling procedures, standards, and test limits.”

Clarified Text

• Clarification #3

Concept Paper Line Number Reference: 1048

Original Text

“Disinfectants should retain efficacy against the normal microbial flora and be effective against spore-forming microorganisms. Many common sanitizers are ineffective against spores, for example, 70%isopropyl alcohol is not effective against Bacillus spp spores. A sporicidal agent should be used regularly to prevent contamination of the manufacturing environment with otherwise difficult to eradicate spore forming bacteria or fungi.”

Note: The text to be modified was narrowed from that present in the working plan with the first sentence in the paragraph being removed. It was determined by the working group that this first sentence was out of scope.

Page 11 of 31 March 13,2003

Aseptic Processing Work Group -Final Report-

Clarified Text

Routinely used disinfectants should be effective against the normal microbial vegetative flora recovered from the facility. Many common sanitizers are ineffective against spores, for example, 70%isopropyl alcohol is not effective against Bacillus spp spores. Therefore a sound disinfectant program should also include a sporicidal agent, used according to a written schedule, and if environmental data suggests the presence of bacterial spores.

• Clarification #4

Concept Paper Line Number Reference: 1055

Original Text

“After the initial assessment of sanitization procedures, ongoing sanitization efficacy should be frequently monitored through specific provisions in the environmental monitoring program, with a defined course of action in the event samples are found to exceed limits.”

Clarified Text

Once sanitization procedures are established, adequacy is evaluated through the routine environmental monitoring program.

• Clarification #5

Paper Line Number Reference: 1070

Original Text

“Manufacturers should be aware of a device's air monitoring capabilities, and should determine suitability of any new or current devices with respect to sensitivity and limit of quantification”

Clarified Text

Manufacturers should be aware of a device's air monitoring capabilities, and the air sampler should be evaluated for its suitability for use in an aseptic environment based on cleanability, ability to be sterilized, and disruption of unidirectional airflow. Manufacturers should assure that it is calibrated and used according to instructions. Because these attributes vary from device to device, the user should assess the suitability of all monitoring devices before they are placed into service.

• Clarification #6

Concept Paper Line Number Reference: 1419

Original Text

“Multiple material transfers are generally made during the processing of a batch. Frequently, transfers are performed via direct interface with a decontaminating transfer isolator or dry heat depyrogenation tunnel with balanced airflow. Such provisions, if well designed, help ensure that microbiological ingress does not result from the introduction of supplies. Properly operated RTPs (rapid transfer ports) are also generally considered to be an effective transfer mechanism. The number of transfers should be kept to a minimum because the risk of ingress of contaminants increases with each successive material transfer.”

Clarified Text

Multiple material transfers are generally made during the processing of a batch. Frequently, transfers are performed via direct interface between manufacturing equipment and properly maintained and operated rapid transfer ports (RTPs) are an effective mechanism for aseptic transfer of materials into and out of isolators.

Page 12 of 31 March 13,2003

Aseptic Processing Work Group -Final Report-

Note: During the review the working group concluded that the last sentence of the text to be clarified (“The number of transfers should be kept to a minimum because the risk of ingress of contaminants increases with each successive material transfer.”) should be revised and moved into Line 275 of the concept paper. This location represents the best location fit for the information.

Added Clarification text (concept paper reference Line 275).

…surrounding environment. The number of transfers into an isolator or the critical zone of a clean room should be minimized.

• Clarification #7

Concept Paper Line Number Reference: 1033

Original Text

Clarified Text

Significant changes in microbial flora should be considered in the review of the ongoing environmental monitoring program.

• Clarification #8

Concept Paper Line Number Reference: 981

Original Text

Clarified Text

Evaluating the quality of air and surfaces in the cleanroom environment should start with a well-defined written program and scientifically sound methods. The monitoring program should cover all production shifts and include air, floors, walls, and equipment surfaces, including the critical surfaces in contact with product and container/closures.

Page 13 of 31 March 13,2003

Aseptic Processing Work Group -Final Report-

PQRI

Aseptic Processing Working Group

Recommendations

- Report- (Approved by the PQRI Steering Committee March 11th, 2003)

Page 14 of 31 March 13,2003

Aseptic Processing Work Group -Final Report-

RECOMMENDATION #1

Concept Paper Line Number Reference: 661

Question: What is an appropriate number of units to be filled during process simulation (media fill)?

Recommendation:

• The number of units to be filled should be sufficient to accurately simulate activities that are representative of the manufacturing process. Such activities include but not limited to:

Aseptic manipulations during setup and during production Interventions – type and appropriate number o Typical/Routine o Atypical/Non-Routine Staffing Levels Shift Changes Gown Changes Multiple day fills

• A generally acceptable starting point is between 5,000 to 10,000. For batch sizes under 5,000 the number of media filled units should equal the batch size.

• Where the technology is such that the possibility of contamination is higher (manually intensive filling lines), a larger number of units, generally at or approaching the full batch size, should be considered.

Rationale:

• The number of units filled during the process simulation should be based on contamination risk for a given line, and sufficient to accurately simulate manufacturing operations. For instance, a process conducted in an isolator can have a very low risk of contamination because of the lack of human intervention, while a manual (or highly manual) aseptic process has a higher risk of contamination. In these instances, the isolated process may be simulated by filling a lower number of units as a proportion of the overall operation versus a manual operation that would fill the maximum number of units.

Survey Data Summary:

• Number of units filled during the process simulation compared to production batch sizes.

Mfg. Lot Size 5,000 units and under ≥Lot size 92%

Mfg. Lot Size 5,001 – 10,000 >75% of lot size 33% 50% to 75% of lot size 63% <50% of lot size 4%

Mfg. Lot Size 10,001 – 20,000 >75% of lot size 28% 50% to 75% 25% <50% 47%

Mfg. Lot Size20,001 – 40,000 >75% of lot size 1% 51% to 75% 3% 25% to50% 49% <25% 47%

Page 15 of 31 March 13,2003

Aseptic Processing Work Group -Final Report-

Mfg. Lot Size 40,001 – 80,000 >75% of lot size 6% 51% to 75% 2% 25% to50% 18% <25% 74%

Mfg. Lot Size >80,000 >75% of lot size 0% 51% to 75% 0% 25% to50% 9% <25% 90%

• Distribution for the total number of media units filled.

Media Fill Lot Size <5,000 23%

Media Fill Lot Size 500110,000 38%

Media Fill Lot Size 10,00120,000 28%

Media Fill Lot Size >20,000 11%

• Average number of media units filled; 12,981

Page 16 of 31 March 13,2003

Aseptic Processing Work Group -Final Report-

RECOMMENDATION #2

Concept Paper Line Number Reference: 730

Question: What is an acceptable temperature range for the incubation of media fill units using TSB and FTM? If alternative practices are used what type of justification is required?

Recommendation:

• Incubation temperatures should be suitable for recovery of bioburden and environmental isolates.

• Incubation conditions should be not less than 14 days at either a temperature or temperatures between 20- 35°C. If two temperatures are used for the incubation of the media filled samples, these filled samples should be incubated for at least 7 days at each temperature.

• The incubation temperature should be maintained within 2.5oC of the target temperature. The temperature should at no time be below 20oC or above 35oC.

Rationale:

• The temperature range provided is suitable for the recovery of wide range of mesophilic bacteria (the largest portion of bacteria are classified as mesophilic). The temperature range is similarly suitable for a wide range of yeast and molds.

• The recommendation is consistent with current USP, PDA, and PIC/S guidance.

• Regarding the second part of the rationale question. No specific temperature was selected as a set temperature to allow flexibility for the individual firms to select the temperature range(s) appropriate for their operation. The justification for all temperatures is specified in bullet one.

• The survey data indicates that industry currently uses various incubation conditions that can recover a wide range of mesophilic flora. The recommendation provides for the use of these different approaches.

References:

• PDA Technical Report No. 22, “Process Simulation Testing for Aseptically Filled Products” 1996.

• PIC/S, “Recommendation on The Validation Of Aseptic Processes,” April 2000.

Survey Data Summary:

• What is temperature range does your firm currently use for the incubation of media fill units? Number of respondents =49

A 20-25 o C 1 2% B 25-30 o C 1 2% C 30-35 o C 3 6% D 20-25 then 30-35 o C 24 49% E 30-35 then 20-25 o C 7 14% F other (specify) ______13 27%

Page 17 of 31 March 13,2003

Aseptic Processing Work Group -Final Report-

2 30-32C 5 A + C 1 28C 1 28-32C 1 A + D 1 C + E 1 C + D 1 NA (small batch)

Page 18 of 31 March 13,2003

Aseptic Processing Work Group -Final Report-

RECOMMENDATION #3

Concept Paper Line Number Reference: 787

Question: What is an appropriate limit for the contamination rate in a process simulation (media fill)? What is an appropriate target for contaminated units in a process simulation (media fill)?

Recommendation:

• The target is zero contaminated units.

• Any contaminated unit indicates a potential sterility assurance problem, regardless of run size. All contaminated units should result in a thorough, documented investigation.

• Clear acceptance criteria should be established for media fills.

• The following criteria are generally acceptable:

When filling less than 5000 units no contaminated units should be detected.

When filling from 5,000 to 10,000 units 1 contaminated unit requires an investigation and a determination if any further action is needed such as a repeat of the media fill. 2 contaminated units are considered cause for revalidation following investigation.

When filling more than 10,000 units 1 contaminated unit requires an investigation 2 contaminated units are considered cause for revalidation following investigation.

• Recurring incidents of contaminated units from media fills for an individual line, regardless of the set acceptance criteria, should be a signal that action should be taken.

Rationale:

• With older technology, standard manufacturing operations were normally easily simulated in small media fills. In 1973, the World Health Organization recommended demonstrations of less than 0.3% contamination, which could be demonstrated with a fill of as low as 1,000 or 2,000 containers. By 1980, PDA Technical Monograph #2 suggested demonstration of less than 0.1% contamination, which was also adopted by the FDA in their 1987 Guideline on ‘Sterile Drug Products Produced by Aseptic Processing’, requiring media fills of 3,000 units or more (using the 95% confidence interval statistical approach). This size was considered a minimum because the absence of growth was evidence of contamination at a rate of less than 0.1%.

• In these examples, the expression of acceptance based on a percent contamination was meant to provide a standard based on the realistic limitations of media fills of these sizes. However, the use of percent contamination in these examples was not meant to provide a tolerance for greater contamination in larger media fills. The 0.1% tolerance was linked to the detectable limit of the test using 3,000 units. For this reason, larger media fills should be subject to acceptance criteria that are not linked to percent contamination.

• Limits based on statistical calculations have been demonstrated to be flawed for aseptic operations, in part because it is not appropriate to apply the statistics of large-scale populations to smaller ones. A statistical

Page 19 of 31 March 13,2003

Aseptic Processing Work Group -Final Report-

approach makes faulty assumptions that the distribution and frequency of potentially contaminated units are the same in these populations. Statistically-derived contamination rates are therefore not relevant in setting acceptance criteria for process simulations.

• The target for contaminated units should be zero, which is consistent with the definition of sterile products. This is commensurate with data indicated in the PQRI survey.

• A phased approach is appropriate for simulations above the minimum number of 5,000 units, as likelihood of detection will increase with simulation size. An isolated incident (no trend) in which one contaminated unit beyond the 5000 unit level is detected may be considered a random event. This should however, require an investigation and assessment for repeat, whereas more than one contaminated unit may be more indicative of an issue that needs to be resolved.

References:

• FDA, “Sterile Drug Products Produced By Aseptic Processing”, 1987 • EU GMP Annex 1, “Manufacture Of Sterile Medicinal Products” • PIC/S, “Recommendation on The Validation Of Aseptic Processes,” April 2000.

Survey Data Summary:

• Percentage of Media fills with contamination.(606 Media Fills Total)

Contaminated 9%

Not Contaminated 91%

Page 20 of 31 March 13,2003

Aseptic Processing Work Group -Final Report-

• Breakdown of Contaminated Media Fills (54 of 606 runs contaminated).

1200 Contaminations 2%

5 Contaminations 4%

4 Contaminations 15%

3 Contaminations 7%

2 Contaminations 6% 1 Contamination 66%

Page 21 of 31 March 13,2003

Aseptic Processing Work Group -Final Report-

Recommendation #4

Concept Paper Line Number Reference: 981

Question: When should critical surfaces be monitored? What are appropriate expectations in regards to results obtained?

Recommendation: • The selection of sample sites should be strategic in an environmental monitoring program. This should include consideration as to when, or if a critical site should be monitored. • Each manufacturer should review each type of process and the points of risk for product contamination. Consideration should be given to the level of contamination risk based on factors such as: difficulty of setup; length or processing time; impact of interventions, etc. • It is well understood that the sampling and incubation methods used in surface monitoring are manual operations that, due to personnel involvement, results in a low rate of false positives. For this reason, the detection of microorganisms on a critical site should not necessarily result in batch rejection, but should be investigated. The other EM data and procedures, that support the operation, should be reviewed to determine if the positive result is supported. If this review does not support the positive result and there is no negative trend for the critical surface site there is a strong case for not rejecting the lot due to the positive result. • PQRI strongly supports the concept discussed on line 993 of the concept paper; that, when performed, “Critical surface sampling should be performed at the conclusion of the aseptic processing operation to avoid direct contact with sterile surfaces during processing.”

Rationale:

• The strategic monitoring of critical surfaces can provide useful data on the state of environmental control within the aseptic processing area. It can allow adverse trends to be detected, investigated and corrected promptly. • Environmental monitoring is performed in an environment that does not afford the same controls as that present in sterility testing. For this reason the testing cannot be used to determine the sterility of the product. Occasional positive results are expected due to the involvement of EM monitoring personnel during sampling and as a result of sample handling and incubation within the laboratories. • The sampling process requires contact with the critical surface (e.g., Rodac sample). To reduce the possible negative impact this activity has on the critical areas, it should be performed at the conclusion of the processing operation.

Survey Data Summary:

• When does your firm perform environmental monitoring on critical surfaces (product contact surfaces)? Number of respondents = 49

A at beginning of operations 0 0% B during operations 7 14% C conclusion of operations 26 53% D not monitored 4 8% E other (add specific comment) 12 24%

1 B + C 4 A + B + C

Page 22 of 31 March 13,2003

Aseptic Processing Work Group -Final Report-

1 C + D 2 end of media fill 1 C (UK), D (US) 1 do not test product contact surface, sample surface nearby not monitored routinely, only in case of failure investigation

• How does your firm respond when positive results are obtained from critical surface monitoring? (If your firm does not monitor these surfaces go to next question) Number of respondents =49

A automatic rejection 0 0% B investigation 40 81% C no follow-up necessary 0 0% D other (add specific comment) 9 18%

1 not monitored (BFS) 2 less than alert, no action; > alert, investigation 5 NA 1 media fill monitoring of critical surface, if exceed, investigation

Page 23 of 31 March 13,2003

Aseptic Processing Work Group -Final Report-

RECOMMENDATION #5

Concept Paper Line Number Reference: 1014

Question: What data should be considered when initially establishing monitoring limits? What is an appropriate frequency for re-evaluating monitoring limits?

Recommendation:

• Initially, published data and/or historical data from similar operations should be used to set action and alert levels

• Historical data may be derived from areas of similar aseptic operations or represent a homogenization of a company’s monitoring levels, by room class, across lines and facilities.

• For aseptic areas where the allowable levels are less than 1 cfu, consideration should be given to the use of count incidence rates as an indicator of an unfavorable trend.

• Alert and action levels are generally re-evaluated (and re-set if deemed necessary) on an annual basis using primarily the previous years data for setting monitoring levels for the upcoming year. Published data should be considered when re-evaluating the action level.

Rationale:

• There are no US regulations stipulating environmental action levels. However, published data should be considered when setting action levels to assure that historical data-based action levels do not slowly creep beyond generally accepted levels.

• Remedial action to exceeding alert or actions levels in all room classes should be taken based on unfavorable trends as opposed to individual data point excursions. This is particularly true (and difficult to accurately measure) for ISO Class 5 aseptic areas where the action level is 1cfu/m3.

• The frequency at which monitoring levels are re-evaluated is somewhat dependant on the frequency at which the line is used. It may take additional time to gather sufficient data to re-evaluate lines that are seldom used.

Survey Data Summary:

• What data does your firm consider when initially establishing monitoring limits for a new area? # Respondents Yes No A. Historical databases 49 39 (80%) 10 (20%) B. Cleanroom qualification 45 35 (78%) 10 (22%) C. Sanitization studies 46 15 (33%) 31 (67%) D. Publications 49 45(92%) 4 (8%) E. Media fills 47 16 (34%) 31 (66%) F. Relationship of monitoring location to overall operation 46 33 (72%) 13 (28%) G. Other (add specific comment) 0

Page 24 of 31 March 13,2003

Aseptic Processing Work Group -Final Report-

• What data does your firm consider when reevaluating monitoring limits for an existing area? # Respondents Yes No A. Historical databases 47 45 (96%) 2 (4%) B. Cleanroom qualification 45 21 (47%) 24 (53%) C. Sanitization studies 45 15 (33%) 30 (67%) D. Publications 44 35 (80%) 9 (20%) E. Media fills 44 19 (43%) 25 (57%) F. Relationship of monitoring location to overall operation 45 26 (58%) 19 (42%) G. Other (add specific comment) 0

• What frequency does your firm use for re-evaluating environmental monitoring limits? Answer in number of months between reevaluations, e.g., 6, 12, 18, 24, etc. Number of respondents = 47

Frequency 6 mo. 1 (2%) 12 mo. 33 (70%) 18 mo. 0 (0%) 24 mo. 5 (11%) Other: 8 (17%)

2 5 yr. 1 12-18 mo. 1 6 and 12 mo. 1 12 and 24 mo. 3 no SOP

Page 25 of 31 March 13,2003

Aseptic Processing Work Group -Final Report-

Recommendation #6

Concept Paper Line Number Reference: 82

Question: What is the maximum number of viable organisms allowed in air samples for the various classifications?

Recommendation: • The document should be standardized to the ISO designations. • The air classification table should only use metric units for the microbial action levels. • Replace the term “limits” in the table with “Action Levels”. • Add Microbial Settling Plates to Harmonize with EU Annex 1

TABLE 1- Air Classificationsa

Clean Area ISO > 0.5 um Microbiological Microbiological Classification Designation particles/m3 Action Levelsb Settling Plates cfu/m3 Action Levelsb,c (diam. 90mm) cfu/4 hours 100 5 3,520 1d 1d 1000 6 35,200 7 3 10,000 7 352,000 10 5 100,000 8 3,520,000 100 50

a- All classifications based on data measured in the vicinity of exposed articles during periods of activity. b- Alternate microbiological standards may be established where justified by the nature of the operation. c- The use of settling plates are optional. d- Samples from class 100 environments should normally yield no microbiological contaminants.

• Remedial action when exceeding actions levels in all room classes should be taken based on unfavorable trends (intra and inter day) as opposed to individual data point excursions. For example, in the Class 100 areas a single action may not require a corrective action after a review of EM trend data for the area.

Rationale:

• The recommended modifications to the table harmonize it with international standards and reflect the most current published standards.

• The incorporation of the term “action levels” clearly convey that the numbers provided are not product related specifications but levels that when exceeded must be investigated.

• Note: ISO class 5 is approximately equal to EU Grade A.

References:

• <1116> Microbiological Evaluation of Clean Rooms and Other Controlled Environments, USP 24, United States Pharmacopeial Convention, Inc., Rockville, MD, 1999. • PDA Technical Report No. 13 (Revised), “Fundamentals of an Environmental Monitoring Program” Sept/Oct 2001. • ISO 13408-1, “Aseptic Processing of Health Care Products- Part 1: General Requirements,” August 1, 1998.

Page 26 of 31 March 13,2003

Aseptic Processing Work Group -Final Report-

• ISO 14644-1 “Cleanrooms and associated controlled environments – Part 1: Classification of air cleanliness”, 1999. • EU Annex 1

Survey Data Summary: • What air microbial action level does your firm use for your Class 1,000 area? Answer in number of CFU per cubic meter. Number of respondents =47

facility has a class 1000 area 10 21% no class1000 area 37 79%

• What action level is used (CFU/m3 ) for class 1000 area:

(<0.0042, 1, 3, 4, 6, 7, 10, 15, 18)

Page 27 of 31 March 13,2003

Aseptic Processing Work Group -Final Report-

RECOMMENDATION #7

Concept Paper Line Number Reference: 1369

Question: What type of airflow is required in a closed isolator?

Recommendation:

• The section needs to recognize, up front, that there are two major ‘types’ of isolators; open and closed. • The term “Unidirectional” in 1369 should be split out for open isolators. • Within a closed isolator turbulent flow is normally acceptable. • The terms open isolator and closed isolators should be better defined. Recommend that the definitions be based on those contained in PDA Technical Report No. 34. Rationale:

• It is important that open and closed isolators be differentiated between in the document since they have different operational expectations. Open isolators are characterized by an interface between the external and internal environments (i.e., to allow ingress of sterile vials and/or egress of filled vials), and therefore, uses elements of conventional clean room technology (i.e., pressure differentials and unidirectional flow air) to provide assurance of environmental quality. Closed isolators have no such openings and therefore generally do not require unidirectional airflow.

Survey Data Summary:

• What type of airflow is required at your firm for closed isolators? Number of respondents =14

A unidirectional 8 (57%) B turbulent 6 (43%)

NOTE: Some question was raised, in regards to the survey results, if those reporting unidirectional airflow in close isolators truly had unidirectional flow.

Page 28 of 31 March 13,2003

Aseptic Processing Work Group -Final Report-

RECOMMENDATION #8

Concept Paper Line Number Reference: 1372

Question: What is the appropriate recommendation for air handling systems in isolators?

Recommendation:

• Redundant HEPA (or ULPA) filters, in series, are not necessary.

• The document should not specify the type of filter to be used to reduce the microbial load of the air entering isolator.

• Suggest the following wording... “The air handling system should be capable of maintaining the requisite environmental conditions within the isolator”

Rationale:

• Redundant filters HEPA (or ULPA) are also not required for traditional aseptic processing areas; therefore, there should be no a priori requirement to use them to maintain the environment of an isolator.

• Multiple types of filters and potentially new technologies can be used for this purpose. The purpose of these filters is to insure air entering the isolator meets environmental requirements.

• The important point is that we control ingress and egress of everything entering and exiting the isolator (air, components, etc.) to insure maintenance of a suitable environment for assurance of sterility of the products of aseptic processing. How we do it is less important.

Survey Data Summary:

• Does your firm use ULPA and HEPA filters installed in series on its isolator system? Number of respondents =14

Yes 6 (43%) No 8 (57%)

• If you answered "no" to the last question, do you have multiple pre-filters, including one that is at least 95% ASHREA-rated, preceding the single terminal HEPA or ULPA? Number of respondents =12

Yes 9 (75%) No 3 (25%)

Page 29 of 31 March 13,2003

Aseptic Processing Work Group -Final Report-

RECOMMENDATION #9

Concept Paper Line Number Reference: 1448

Question: What are appropriate methods for use in the development of decontamination cycles?

Recommendation:

• Isolators should be decontaminated with a sporicidal agent. The decontamination cycle needs to be qualified.

• Normally, a 4 – 6 log reduction can be justified depending on the application. The specific BI spore titer used and the selection of BI placement sites should be justified.

• All product contact surfaces, within the isolator should be sterilized, i.e., demonstration of 6 log reduction of suitable BIs.

• Chemical indicators and fraction negative studies can be used to help develop a decontamination cycle. However, demonstration of suitable kill of BIs is the ultimate standard.

• It is important to ensure uniform distribution of the decontaminating agent during cycle development.

• Recommend that no change is made in the statement regarding fraction negative studies.

• Clarify various materials statement to stress texture and porosity rather than composition.

Rationale:

• The environment within an isolator is not purported to be sterilized. Sterilization, in this instance, would be an imprecise technical term. The internal environment is decontaminated to ensure a suitable environment for aseptic processing.

• Requirements for isolators should not be greater than for conventional areas used for the same function. Just as with conventional filling areas the use dictates the acceptable decontamination requirements and environmental expectations.

Survey Data Summary:

• What method/s does your firm use in the development of decontamination cycles?

total kill analysis Number of respondents =21 Yes 16 (76%) No 5 (24%) half-cycle Number of respondents =18 Yes 10 (55%) No 8 (45%) fraction negative Number of respondents =17 Yes 7 (41%) No 10 (59%)

Page 30 of 31 March 13,2003

Aseptic Processing Work Group -Final Report-

Recommendation #10

Concept Paper Line Number Reference: 57

Question: With respect to terminal sterilization and adjunct processing what flowcharts represent the most risk- based and scientifically developed approach?

Recommendation: • No detail should be added to the current text present in the concept paper.

• The comment beginning on line #56 regarding adjunct processing should be reworded to clearly indicate that adjunct processing is not an expectation at this point.

• The group strongly recommends to PQRI that a group be formed within PQRI or another organization to further discuss and develop this topic.

Rationale:

• This topic involves adjunct processing being used in conjunction with aseptic processing as a general concept to increase sterility assurance. As indicated by the survey the topic of adjunct processing has value and should be explored. However, it will need to be further developed before it can be included, on a scientific basis, in a guidance document. Added scientific discussion, research, and the establishment of new standard methods will be needed to understand how it might be used and what expectations from a regulatory perspective should be considered. • Since terminal sterilization is far better understood, a firm should not default automatically to aseptic processing but should explore terminal sterilization during product development.

Survey Data Summary:

• What of the following flowcharts represent the most risk-based and scientific development approach? [Pick only one.] Number of respondents =44

A terminal sterilization (explore heat methods only) -> aseptic processing 12 27% B terminal sterilization (explore heat and irradiation methods) -> aseptic Processing 7 16% C terminal sterilization (explore heat methods only) -> consider adjunct process -> aseptic processing 5 11% D terminal sterilization (explore heat and irradiation methods) -> consider adjunct process-> aseptic processing 14 32% E automatically default to aseptic process without any studies 6 14%

• What percentage of sterile products at your firm are aseptically filled and could be terminally sterilized (capable of withstanding Fo > 8 minutes without change in current packaging and formulation)? [Enter a number as a percentage.] Number of respondents = 49

0% 36 2% 2 5% 2 10% 4 20% 1 30% 2 don’t know 2

Page 31 of 31 March 13,2003