# Presentation: 279791

## Synopsis of 1987 Aseptic Processing Guidance Revision

## Updating the Aseptic Processing Guidance

- Original 1987 Guidance Document:
- Written circa 1980 in lieu of regulations
- Guidance route provided latitude
- Need for updated CGMP guidance on high risk area of sterile drugs

## Updating the Aseptic Processing Guidance

- General Objectives of Updated Manufacturing Guidance
- Reflect evolution of knowledge
- Incorporate latest scientific principles
- Remove obsolete information
- Address newer technologies
- Reflect current standards
- Fill major voids illuminated over time

## Updating the Aseptic Processing Guidance  

- Updated Manufacturing Guidance
- Has been requested by Industry
- Promotes better CGMP understanding
- Facilitates compliance
*Proactive communication of expectations for firms building or modifying facilities saves money*
*Clarifies issues for which questions persist*

## Updating the Aseptic Processing Guidance  

- Persistent issues can be resolved and averted
- Appropriate clarifications will help prevent recurring, time consuming problems (for both FDA and the Industry)
- Predictability and Consistency

## Risk-Based Approach Sterile Drugs 	

- Failure to adhere to CGMPs can impact product safety and efficacy
- Hazards to the Product
- Are also hazards to a patient
- Unacceptable risk to patients posed by contaminated drug
- Top priority of risk-based program
- Guidance emphasizes risk-based CGMP approaches
- e.g., environmental monitoring

## Updating the Aseptic Processing Guidance 

**Innovation:**
- Concept paper acknowledges process improvement through use of:
*Modern facility/equipment design  *
*Automation*
*Well-conceived (e.g., airlocks, appropriate ergonomics/layout)*
*New Technologies  *
*including reduction of direct personnel involvement in aseptic operations via isolation technology and barrier concepts *
**Latitude:**** **
- Liberalizing some old standards
*e**.g., velocity (FPM); BFS microbial air quality stressed *

## Updating the Aseptic Processing Guidance 

- Advantages to those:
*Enhancing product protection and safety, through use of automation and aseptic process barrier/isolation concepts*
*Following sound CGMP operating procedures & defining good process metrics *
- Quality/Business Synergies

## Risk-Based Approach  Critical Control Points

**Causes of Contamination**
*Where are the potential routes of contamination in an aseptic process?*
**Detection of Contamination Problem**
*What measurements are most valuable in indicating sterility assurance?*
**Focus on issues of concern**
*Focus should be on assessing and addressing factors that influence control of the facility and process*

## Updating the Aseptic Processing Guidance 

- Updating the Aseptic Processing Guidance

- Format Improved
- More user friendly
- Table of Contents, Headings
- Easier to read and follow
- New Definitions Added
- air lock, components, colony forming unit, dynamic, endotoxin, gowning qualification, barrier, isolator, etc.
- Old Sections
- Updated old sections (e.g., sterilization)
- New Sections
- e.g., personnel, isolators, early processing

## ADVISORY COMMITTEE MEETING COMMENTS

- Consensus that the draft guidance should be published promptly
- Use of Latitude Phrases
- Too much latitude can mean too little guidance
- More detail needed in some instances
- Media Fills -  key clarifications needed (e.g., acceptance criteria)
- FDA’s positive comments on Isolators appreciated by industry

## ADVISORY COMMITTEE MEETING COMMENTS

- Include acknowledgement of appropriate rapid methods as alternative to traditional methods
- reflect FDA open-mindedness to these new  methods
- Action Limits vs. Action Levels
- PQRI recommended for resolution of  major issues

## PQRI Aseptic Processing Workgroup

## PQRI Aseptic Processing 

**Working Group**

- Formed to provide scientifically based input into the FDA’s concept paper on aseptic Processing.
- Working Group’s activities targeted at specific aseptic processing topics.
- Comprised of members from FDA, Industry, Academia

## Working Group Members

- _ _

**James P. Agalloco**, Agalloco & Associates
**James E. Akers**, Ph.D., Akers Kennedy & Associates
**Barbara Bassler**, Bridge Associates International
**Martyn Becker**, Merck & Co.
**Susan Bruederle**, FDA
**Don Burstyn**,** **Ph.D., Alkermes
**Roger Dabbah**, Ph.D., USP
**Roger Deschenes**, Astra Zeneca
**Joseph Famulare**, FDA
**William R. Frieben**, Ph.D.,Pharmacia Corporation
**Rick Friedman**, FDA
**John G. Grazal**, AstraZeneca Pharmaceuticals
**Klaus Haberer**, Ph.D., Compliance Advice & Services
**Nigel Halls**, Ph.D., GlaxoSmith Kline (ret.)
**Karl L. Hofmann**, Brystol-Myers Squibb Co.
**David Hussong**, Ph.D., FDA
**Richard M. Johnson**, Abbott Laboratories
**Kunio Kawamura**, Ph.D., Otsuka Pharma. Co., Ltd.
**Lee Kirsch**, Ph.D., University of Iowa
**Carol M. Lampe**, Baxter Healthcare Corporation

**Joe Lasich**, Alcon Laboratories, Inc.
**Carol M. Lampe**, Baxter Healthcare Corporation
**John Lindsay**, Aseptic Solutions Inc.
**Russell E. Madsen**, PDA
**Andy Minor**, Eli Lilly & Co.
**Leonard Mestrandrea**, Ph.D., Pfizer Inc.
**Kenneth Muhvich**, Ph.D., Micro-Reliance.
**Terry Munson**, KMI/PAREXEL, Inc.
**Rainer F. Newman**, Johnson & Johnson
**Jean I. Olsen**, GlaxoSmithKline
**Carolyn Renshaw**, FDA
**Robert Sausville**, FDA
**Neal Sweeney**, Ph.D., FDA
**Ian D. Symonds**, GlaxoSmithKline
**Laura Thoma**, Ph.D, University of Tennessee
**Debbie Trout**, FDA
**Martin Van Trieste**, Abbott Laboratories
**Brenda Uratani**, FDA
**Richard T. Wood**, Ph.D., Pfizer, Inc.
**Glenn E. Wright**, Eli Lilly & Co.
**Jeff Yuen**, Jeff Yuen and Associates

## Working Group Goals

- Develop, execute, and compile an industry survey to poll current industry practices on Aseptic Processing.
- Develop redline clarifications for 8 text areas within the concept paper.
- Develop recommendations on 10 specific topics.
- Complete all activities by Feb 28, 2003.

## Basis of Recommendations to FDA

- Collective experience of the workgroup
- Data from survey
- Scientific Publications (e.g., journal papers)
- Other references (PIC, other regulatory documents)

## Project Timeline (actual)

**Nov ****	****20, ****	****2002  ****	****Working Group Formation Approved**
**Dec ****	****23, ****	****2002  ****	****Work Plan and Survey Approved**
**Jan ****	****9, ****	****2003****	****First Meeting of Working Group**
**Feb 3,****	****2003 ****	****Clarifications Completed**
**Feb****	****28, ****	****2003****	****Last Meeting**
**Mar****	****6,****	****2003****	****Recommendations Completed**
**Mar****	****10, ****	****2003****	****Report Approved**

**110 Days**

**76 Days**

##  Clarifications

## Clarifications #1

- _(Concept Paper Line Number Reference: 637)_

## Clarifications #5

- _(Concept Paper Line Number Reference: 1070)_

## Clarifications #7

- _(Concept Paper Line Number Reference: 1033)_

##  Recommendations

## Recommendation #1 

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

- 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
-   	Typical/Routine
-   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.

## Recommendation #1 

- 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.

- (Continued)

## Recommendation  #2

- Incubation temperatures should be suitable for recovery of bioburden and environmental isolates.
- Incubation conditions should be NLT 14 days at either a temperature or temperatures between 20-35°C. If two temperatures are used for incubation of the media filled units, they should be incubated for at least 7 days at each temperature.
- The incubation temperature should be maintained within 2.5oC of the target temperature, and at no time below 20oC or above 35oC.

**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 #3

**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)?**

- Target is zero contaminated units.
- Any contaminated unit indicates a potential sterility assurance problem.  All contaminated units should result in a thorough, documented investigation.
- Recommended acceptance criteria should be established for media fills.
- 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.

## Recommendation #3

- 	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.

**Recommendation #3**

- (Continued)

## Recommendation #4 

- 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.
- 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.

**When should critical surfaces be monitored? What are appropriate expectations with regard to results obtained?**

## Recommendation #4(cont’d) 

- 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 set-up; length or processing time; impact of interventions, etc.
- 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.”

## Recommendation #5 

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

- 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.

## Recommendation #6

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

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

## Recommendation #6

- (Continued)

## 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. 

- 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.

**Recommendation #7**

**What type of airflow is required in a closed isolator?**

## Recommendation #8 

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

- 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”**

## Recommendation #9

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

- 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.

## Recommendation #9

- 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.

- (Continued)

## Recommendation #10

- 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.

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

## PQRI Working Group Summary

- The Aseptic Processing Working Group has completed its activities as specified in the approved work plan.
- The final report is available on the PQRI Website at www.PQRI.org.
- The principal reason for the success of this working group was the expertise of its members.
- The PQRI process clearly demonstrates that when we bring together true experts and base are discussions in science we can work together to develop guidance that is good for the Regulators, the Industry, and the Consumer.

## Status of Guidance Revision

**Concept Paper****  **
- CDER / CBER / ORA document posted on FDA website on 9/27/02
**Advisory Committee Meeting** **Held 10/22/02**
- revisions made based on input from meeting
**PQRI Aseptic Processing Working Group **** **
- completing revisions based on PQRI  recommendations
**Next Steps**** **
- regulatory/legal review
- publication of draft guidance for public comment