# Presentation: 209533

## FDA Preliminary Concept PaperSterile Drug Products Produced by Aseptic Processing 

- This presentation summarizes the content of PDA’s official position, presented to the PSAC in the report “PDA Comments Prepared for the Pharmaceutical Science Advisory Committee Meeting on October 22, 2002 on FDA Preliminary Concept Paper Sterile Drug Products Produced by Aseptic Processing”

**Notes:**
We at PDA know that it is very difficult to get such documents to an approvable
state.
After all, we are in the business of writing technical monographs and
getting them approved by a diverse bunch of smart people with varing opinions.
And , those of us in industry and academia also serve on policy setting
committees and fight these battles day to day.
Therefore, we greatly appreciate the persistence and the effort the agency
has shown. 

Every time we publishz a new technical report there are two criticisms: it is too
specific, and, guess what - it is not specific enough.

We also appreciate the creativity the agency has demonstrated to publish this in
the way they have as a Concept Paper to further the dialogue  among all
interested parties.  We are seeking this dialogue, and we believe it is essential
to get the best possible work product.  We applaud the fact that FDA has chosen
 to make the paper public at this time and we are excited for the next steps.

## Introduction

- Positives:
- Revision of the aseptic processing guidance issued by FDA in 1987 is overdue
- Supports advantages of isolators relative to conventional, manned aseptic processing
- Provides the framework for open dialog with the agency
- At this stage, is not intended for use by the field

**Notes:**
PDA believes the concept paper contains guidance useful to pharmaceutical companies and FDA field investigators.  The guidance should enable inspected firms to know what to expect during FDA inspections of their aseptic processing areas and eliminate observations based on hearsay, outdated guidance or expectations resulting from what other firms did to comply with arguably overzealous FDA 483 observations.
There is a desire on the part of most individuals and companies to understand the aseptoc processomg requirements and to comply.  It is important that the final version is very clear on what types of limits and requirements are absolute requirements and what are suggestions where firms have the ability to make good scientific judgments based on the specifics of an operations.  We appreciate that the document does have areas where the need for such judgment is respected.
The concept paper supports the advantages of isolators relative to conventional, manned, aseptic processing.  We believe this will encourage the use of isolation technology by firms that, having lacked guidance, delayed its implementation.
It also provides the needed framework for open dialog with FDA.
Finally, the availability of new guidance should eliminate use by the field of draft guidance which is unavailable to the inspected firms.

## Introduction

- PDA’s Concerns Grouped into Categories
- Best Practices and cGMP
- Technical Issues/Unconventional Terminology
- Scope
- Harmonization

## Best Practices and cGMP

- Departures from Current Industry Practices
- Media fills conducted in ‘worst case’ environmental conditions
- Environmental sampling of critical surfaces that are terminally sterilized
- Isolators do not normally employ unidirectional airflows or redundant HEPA filters
- There is no evidence to support that isolators must be housed in classified areas

**Notes:**
Lines 699-705: “Media fills should be conducted under environmental conditions that simulate normal as well as ‘worst case’ conditions of production.”  We believe media fills, which already tend to be “worst case” because of the growth promotion properties of the medium and the extra manipulation sometimes required, should be conducted under environmental conditions representative of normal production.
Lines 982-984: “The monitoring program should cover all production shifts and include air, floors, walls, and equipment surfaces including the critical surfaces in contact with the product and container/closures.” PDA believes that critical surface monitoring is not advisable because these surfaces are sterilized using validated processes.  Monitoring of theses surfaces provides little meaningful information.  If the results are positive, it could mean the surface contained one or more microorganisms or that it was contaminated by the act of sampling.  Even if negative the result may not be meaningful because of less than perfect recovery efficiency.
Unidirectional airflow is generally unnecessary in closed isolators.  The use of redundant HEPA or ULPA filters is not common practice and is unnecessary.
There is no evidence to support the need to locate an isolator in Class 10,000 or Class 100,000 environments.  PDA believes that isolators should be located in controlled, but unclassified areas.

## Technical Issues /Unconventional Terminology

- References ISO 14664-1 for numerical values for particles per cubic foot, but does not agree with values published therein
- Indicates that membrane filters are used for hot air sterilizer vents, when HEPA filters are used
- States that container-closure systems that permit penetration of air are unsuitable, when many elastomeric closures permit transmission of air/gas
- Defines alert/action limits, text refers to (alert/action) levels for environmental, but does not define the term

**Notes:**
Successful aseptic processing relies on strict adherence to specific, well defined procedures and on accurate knowledge of the critical factors that could result in non-sterile product if not properly controlled.  Correct and consistent use of terminology within the industry and by FDA is critical to success.
The section on air filtration indicates that hot air sterilizer vents should be equipped with membrane filters.  HEPA filters should be used for this purpose.
Particle counts in Class 100 areas should be taken “normally not more than one foot away from the work site,” but the concept paper fails to define work site, leading to unnecessary ambiguity and inconsistent interpretation.
“Airlocks should be installed between the aseptic processing area entrance and the adjoining uncontrolled area.  Other interfaces such as personnel entries, or the juncture of the aseptic processing room and its adjacent room, are also appropriate locations for air locks.”  Modern APAs are not equipped with airlocks between the aseptic filling room and other portions of the APA.
The terms “alert limit” and “action limit” should be changed to “alert level” and “action level.”  Limits are applicable to specifications, while levels apply to process monitoring.  Specification (limits) relates to a direct measurement of product quality that is required to be met by an official monograph or filed application.  Exceeding an alert or action level does not produce an “out of specification” result.

## Scope (Omissions)

- Does not clarify how many units should be filled or allowed positive for a media fill
- Little guidance is provided outside of the APA critical processing zone
- No guidance on CIP/SIP
- Does not provide a systematic, rational approach to aseptic process control and risk assessment

**Notes:**
While the concept paper provides guidance in many areas, two of the most important questions are not addressed, i.e., regarding media fills, how many units should be filled and how many positives are allowed?  Other questions which remain largely unanswered are:
Can a media fill be an exact model of aseptic manufacturing with predictive quality, which can be challenged by going to the extremes? Or is a media fill merely a demonstration that a manufacturer can aseptically fill a pre-determined number of units under a given predetermined set of conditions without introducing detectable contamination?
There is little guidance offered relative to performance of the remainder of the aseptic processing area, outside the critical zone.  Many aseptic processing areas have extensive areas that are either Class B (100 non-unidirectional) or C (10,000).  This is where the personnel are located.  The document should include more detailed guidance for these areas.
CIP/SIP technology although widely used today in aseptic processing is not addressed.
The concept paper fails to provide a systematic, rational approach to aseptic process control and risk estimation.  While buildings, personnel, and components are discussed, there is no clear discussion about how the process should be set up, and how the segregation of product and environment should be accomplished at each step of the process.

## Scope (Topics that should be Excluded)

- Terminal Sterilization
- Endotoxin Control
- Equipment Qualification
- Sterility Testing

**Notes:**
Commenting on the 1987 guideline we said, “The PDA believes that the Guideline should include those aspects of Aseptic Processing which are most likely to affect product quality, namely, the aseptic manipulations made by specially trained personnel during product handling and assembly.  The physical means of sterilization employed by the industry have been validated to deliver sterility assurance levels much greater than those which can be achieved by conventional aseptic processing. . . . The body of technical literature available on the validation of sterilization processes is adequate and considerable, and could simply be referenced by the Guideline.”  These comments are also applicable to the aseptic processing concept paper.
While the concept paper builds on the framework of the 1987 guideline, we believe it should be focused on aseptic processing, i.e., the control and manipulation of sterile components, closures and containers, and the control, monitoring and maintenance of the aseptic processing environment.  Subjects such as endotoxin control, equipment qualification and sterility testing are covered in the literature in great detail.  If FDA believes better information about these subjects is needed, we believe separate guidance documents would be appropriate.

## Harmonization

- The ISO convention for the use ‘should’ and ‘shall’ would greatly clarify requirements from guidance.  Currently ‘should’ is used exclusively and clearly some points are requirements
- Room classifications should be according to ISO standards instead of the obsolete FS209E
- Non-viable particulate values could be harmonized with EU for sample size and limits

**Notes:**
It would be most helpful to know when the document is providing guidance (should) and when it is defining requirements (shall), as these terms are used in ISO documents.
Table 1 and all references to room classifications refer to Federal Standard 209E.  IEST, assigned by the GSA as the Preparing Activity organization for FED-STD-209E, has recommended that International Standard ISO 14644-1 supersede FED-STD-209E, which became obsolete on November 29, 2001.
Lines 108-112: “Air in the immediate proximity . . . is of acceptable particulate quality when it has a per-cubic-foot particle count of no more than 100 in a size range of 0.5 micron and larger (Class 100) when counted at representative locations normally not more than one foot away from the work site, within the airflow, and during filling/closing operations.”  This section needs to be harmonized with EU requirements where sample size and limits are quite different.
Lines 1020-1022: “Each individual sample result should be evaluated for its significance by comparing to the alert or action limits.  Averaging of results can mask unacceptable localized conditions.  A result at the alert limit urges attention to the approaching action conditions.” The EU approach to environmental monitoring is to average results.

## Recommendations

- Concept paper reviewed by ad hoc committee composed of FDA headquarters, ORA and industry (or PQRI subcommittee) to resolve issues
- Committee submits revised document to FDA for review and approval
- Final draft issued for public comment
- Revised aseptic processing guidance issued

**Notes:**
PDA believes the document provides a good platform for a final draft guidance meeting the needs of FDA headquarters, ORA and the regulated industry.  In order to quickly develop a final guidance document, we recommend that the concept paper be reviewed by an ad hoc committee consisting of FDA headquarters and field personnel as well as industry aseptic processing experts.  Another option might be for the ad hoc committee to be formed under the auspices of PQRI.
Media fills are an important component in assuring aseptic processing operations are under control, but even when they consist of filling more than one hundred thousand units over three consecutive shifts, they cannot assure the sterility of the next, or any other production lot.  We need to “break the mold” and find a reasonable alternative to massive media fills.
One possible solution would be to replace process simulation tests, or media fills, with “aseptic process assessments” or “process simulation evaluations,” in which the media fill would consist of a specified number of units, e.g., 10,000, with normal and “atypical” interventions, running under normal line conditions, with a specified acceptance criterion, e.g., NMT one positive.  The media fill would be but one part of the “aseptic process assessment,” which would also include evaluation and documentation of environmental controls, environmental monitoring results, gowning procedures, employee training, room pressure differentials, airflow patterns, maintenance, etc.  This overall evaluation would provide a high degree of assurance that normal aseptic processing operations result in products with high levels of sterility assurance.
We look forward to working with FDA, industry and other professional associations to develop a world-class aseptic processing guidance document.