# Presentation: 033525

##  Sterile Drugs: The Benefits of Risk Analysis 

- Richard L. Friedman, M.S.
*Center for Drug Evaluation & Research*
*Office of Compliance*

## TOPICS

- Aseptic Processing Guidance
-  Risk-based approaches
-  Process consistency
-  Modernization
- Current Sterile Drug Issues
-  Non-sterility case studies

## CGMP in the 21st Century“Sterile Drug Products Produced by Aseptic Processing” (draft)

- Incorporates risk-based approaches
- Promotes innovation
- Encourages use of technologies that increase sterility assurance
- Liberalizes some old standards
- Promotes drug quality
- Clear and consistent communication of regulatory expectations in guidance promotes voluntary compliance with FDA regulations
- Unprecedented outreach:
- Extensive advisory committee, PQRI, industry organization, and public input
- CDER/CBER/ORA consensus document

## Updating the Aseptic Processing Guidance

**CDER/CBER/ORA Concept Paper issued**** **
- posted at** **_www.fda.gov/cder/dmpq_ on 9/27/02
- unprecedented preview of GMP thinking before publishing a draft guidance
**Advisory Committee Meeting - Oct. 22, 2002**
- significant input provided
- revisions made based on input from meeting

## Updating the Aseptic Processing Guidance

**PQRI Aseptic Processing Working Group**** **
- revised following final PQRI recommendations received on 3/19/03
**Advisory Committee Meeting - May 19, 2003**
- Updated manufacturing subcommittee on PQRI process and conclusions
**Draft for Public Comment - Sept 3, 2003**
- _http://www.fda.gov/cder/guidance/1874dft.htm_
**Workgroup Review of Public Comments**
**Final Guidance   **

## Risk

- With few exceptions, formal, systematic approaches are just beginning to be routinely used in manufacturing context
- Risk methods share these basic similarities:
- Estimation of Severity of Risk and Probability of Risk
- Work best when good quality information is available, and it is assessed in multi-disciplinary, science-based, practical manner
- Great advancement for an Agency and Industry making difficult public health decisions often characterized by complexity and uncertainty
*	**	*

## Risk

- Risk Analysis Output = An Estimate
- Objective/Subjective Aspects
- Oversold?
*No.  Risk Analysis is invaluable.  *
*Although it becomes semiquantitative as the system under study becomes complex, good risk analysis still clarifies the picture and promotes development of sound rationales.*
- The value of risk analysis is the systematic approach to evaluation of
- a facility and its overall operation
- a process
- a method
- etc.

## Risk

## Clinical Effects of Drug Contamination

- The most serious outbreaks of infection have often occurred when contaminated products are injected into bloodstream of patients whose immunity is already compromised by their underlying disease or therapy.
- 						 _*Disinfection, Sterilization, and Preservation,*_* Ed. by S. Block, 2001*
- Aging of our population and increasingly aggressive medical and surgical interventions, including implanted foreign bodies, organ transplantations, and xenotransplantation, create a cohort of particularly susceptible persons.”
*	**	**	**Weinstein, Robert A., Nosocomial Infection Update, Emerging Infectious Diseases, CDC, 1998(4);3.  Nosocomial Infection Update*

## Ophthalmic Infections	

*“**Pseudomonas aeruginosa*, the notorious contaminant of eyedrops has caused serious ophthalmic infections, including loss of sight in some cases.  The problem is compounded when the eye is damaged after trauma or ophthalmic surgery.”
- In Sweden: “an outbreak where a hydrocortisone eye ointment caused eight cases of *P. aeruginosa* infection, resulting in impaired vision in five of the patients and necessitating enucleation of the eye in one.
- Ointment contained from 20 to 2000 microorganisms/g
*[*_*Disinfection, Sterilization, and Preservation,*_* Ed. by S. Block, 2001]*

## Why Processes Must be Designed to Prevent Contamination (21 CFR 211.113)

- “The infection dose of microorganisms is not only largely unknown but variable”
-  “...furthermore, it varies not only between and within species but between individual patients.”
- “The symptoms and outcome of medicament-borne infection may be diverse.”
- “Clinical reactions may range from local infection of wounds or broken skin after contact with a contaminated cream, to serious systemic infection such as bacteremia or septicemia from contaminated parenteral products.”
*	**	**	**	**	**	**[*_*Disinfection, Sterilization, and Preservation,*_* Ed. by S. Block, 2001]*

## Microbiological Adaptability and Survivability

- Apollo 12
- Camera retrieved from moon landing over 2.5 years earlier.  Was found to contain bacteria, ID’d by CDC as *Streptococcus mitis*.  Had withstood the intense radiation, desiccation, and cold of space.
- Bottle of Beer rescued from 1825 shipwreck opened under sterile conditions
- Living yeast cells recovered
- 50,000 bottles of beer were then sold using that yeast
*	**	**	**	**	**	**	*
*	**	**	*
*	**	*
*	**	**	**                          **	**	**[*_*Disinfection, Sterilization, and Preservation,*_* Ed. by S. Block, 2001]*

## Importance of Validation and Control

- 	“End product microbiological testing, while providing some information should not be relied upon as the sole justification for the release of the drug product.  The limitations of microbiological sampling and testing should be recognized.”
*	**	*
*	**	**                      **[High Purity Water Systems Inspection Guide, FDA, 1993]*

## 21 CFR 211.113

**	**Sec. 211.113  Control of microbiological contamination.
-     (a) Appropriate written procedures, designed to prevent
- 	objectionable microorganisms in drug products not required to be sterile, shall be established and followed.
-     (b) Appropriate written procedures, designed to prevent  microbiological contamination of drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of any sterilization process.

## 	*Includes both design and maintenance 

- <date/time>

*	***Includes both design and maintenance *

**Daily **
**“****Sterility **
**  ****Assurance”**

**QA/QC**

**Aseptic **
**Processing **
**Line***
** **

**Deviations &**
** ****Environmental **
**Control Trends **
** **

**Disinfection **
**Practices**

**Media Fills**** **

**HVAC/**
**Utilities***

**Process **
**personnel flow**
**material flow**
**layout**
**    **

**Personnel**
** **

**Facility **
**&**
** ****Room***
** **

## Current Issues:Case Studies and Modernization  

## #1: Media Fill Inspection Reliability / Inadequate Investigation 

- Data did not support the acceptability of Media Fill Lot #----.  Initial examination of vials at end of incubation period found 4 contaminated vials out of the 7,800 incubated.   Ten days later, 600 vials from this media fill were re-inspected.  A fifth contaminated vial was found.  All five vials had same isolate, *Micrococcus luteus.    *
- No explanation why all contaminated vials were not removed during first inspection; or why the remainder of the lot (the remaining approx. 7200 vials) was not re-inspected to determine if additional contaminated vials were present.  Quality and Production units did not investigate the fifth positive vial and concluded that the media fill was acceptable.

## #2: Media Fill FailureControl of the Critical (Class 100) Environment

- Media Fill Failures – *Same recurring fungal isolate* common to each of them
- EM systems did not recover this particular microbe before the initial media fill failure
- Subsequent investigation and extended sampling plan identified many instances of this microorganism on multiple locations of the aseptic processing equipment.
- Investigation traced media fill contamination to the failure to adequately clean/disinfect aseptic filling line equipment.

## Modernization Laboratory Tests (TGA on Sterility Testing)

*	****If contamination is to be unequivocally ascribed to adventitious source and a sterility test invalidated:***
*“**It is necessary to employ sensitive typing techniques to demonstrate that a microorganism isolated from the product test is identical to a microorganism isolated from the materials and/or the environment. **While routine biochemical/phenotypical identification techniques can demonstrate that two isolates are not identical these methods are not sufficiently sensitive or reliable enough to provide unequivocal evidence that two isolates are from the same source.”*
*“**Suitably sensitive tests (for example, molecular typing with RNA/DNA homology) are those accepted by microbiologists conducting epidemiological studies to determine that microorganisms are clonally related and have a common origin.  Repeat testing based on the biochemical or phenotypical characterisation of environmental and/or product isolates should not be permitted.”** *
*	**	**	*
*	**	**	**	*
*	**	**	**	**[**TGA – Guidelines for Sterility Testing for Therapeutic Goods, 2002]*

## Modernization Contaminated Media Fill Units are Missed 

- Study: Visual Examination vs. Automated Method
- Automatic inspection of media fill using laser technology
- Microorganisms:
*Staphylococcus aureus* ATCC 6538
*Micrococcus luteus* ATCC
*Aspergillus niger* ATCC 16404
- Automated inspection sorts into two types:
- Units without growth
- Units with possible growth – only this subset is manually inspected by microbiology lab
- False acceptance (during manual inspection) of positive units was demonstrated in the study*	*
*	**	**	**	**[Christensen, A., PDA Annual Meeting, 1999, Washington, DC**]*

## Modernization Study on Media Fill Examination Accuracy 

*Note: First percentage is Manual Detection; Second percentage is Automated Detection*
- *Conventional manual inspection did not detect any of the units inoculated with this microbe.

## SummaryModernization = Risk Mitigation

**Better Design ****  **
- More robust equipment and facilities (e.g., isolators)
- Process predictability is a major theme of CGMPS for the 21st Century
- i.e., for aseptic processing, enhanced contamination prevention practices are yielding more consistent operations
**Improved Testing**
- More rapid problem detection and remedies
**Quality/Business Synergies**
- Robust operational design and good metrics/testing is fundamental to a Good Quality System
- Beneficial to “Design for Quality” from the outset

## References

- CGMPs in 21st Century (Aug., 2002) and FDA Strategic Plan (Aug., 2003); Commissioner’s link at _www.fda.gov_
- _Disinfection, Sterilization and Preservation_, 5th Edition, 2001, edited by Seymour Block
- Claycamp, H.G., “A Perspective on Risk Analysis for the GMP Initiative,” April, 2003, *PQRI Workshop - A Drug Quality System for the 21**st** Century *
- Weinstein, Robert A., “Nosocomial Infection Update,” Emerging Infectious Diseases, Center for Disease Control; 1998(4);3.
- Sundlof, S., FDA Science Forum, April 2003
- “Draft Guidance for Industry Sterile Drug Products Produced by Aseptic Processing,” Food and Drug Administration, August 2003.

## For More CGMP Information...

***Center for Drug Evaluation & Research, ***
***Office of Compliance  ***
***Division of Manufacturing & Product Quality (HFD-320)***
- _[rick.friedman@fda.hhs.gov](mailto:rick.friedman@fda.hhs.gov)_***   ******	******       301-827-9042***
- _[brenda.uratani@fda.hhs.gov](mailto:brenda.uratani@fda.hhs.gov)_***   ******	******       301-827-9024***
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- _[edwin.melendezdiaz@fda.hhs.gov](mailto:edwin.melendezdiaz@fda.hhs.gov)_***   301-827-9006***
- _[karen.hirshfield@fda.hhs.gov](mailto:karen.hirshfield@fda.hhs.gov)_***           301-827-9029***