# Presentation: 547342

## Use of MDCK Cells for Manufacture of Inactivated Influenza Virus VaccinesVRBPAC – 16 Nov 05

**Notes:**
To do:

## Influenza – Disease impact

**Annual winter epidemics**
**10-20% of world population is infected **
**In the US:**
**25-50 million individuals infected**
**>20,000 deaths and >110,000 hospitalizations **
**>$12 billion in direct and indirect health costs**
**Worldwide pandemics **
**1918-19 Spanish Flu: 20-40 million deaths**
**1957 Asian/ 1968 Hong Kong: >1.5 million deaths**

**Notes:**
To do:

## Influenza vaccine – The public need

**Routine Immunization:**
**Recommended for >180 million in U.S. and increasing**
**Current egg-based production for U.S. does not**
**Meet the recommendation**
**Provide flexibility to respond to fluctuating demand**
**Pandemic Immunization:**
**Will require rapid production of vaccine for 6.5 billion worldwide, ~300 million people in the US**

**Notes:**
To do:

Talking Points:
Mention ’05 supply limitations for 50% of target population, or 80MM
Cite Chiron in supply problems?

Backups:
3-1 Backup for numbers that add to 180MM (Oliver/Bill)
3-2 Current US MFG capacity slide.  Check HHS statements on capacity constraints (Ulrich to send to CAL)
3-3 Pandemic capacity requirement backup slide – 300MM doses/courses, data from NIH studies, dose sparing (uncertainty) (Harmon/Podda)
3-4 Why egg-based not possible for pandemic.  No chickens and/or lethal to eggs. (Ulrich)
3-5 Reengineering takes time (how much?) (Dietmar)

## Influenza vaccine – Egg-based process and risk

- 1x

- ~ 1x

**Production Time**
**6+ Months**

**Egg Lead Time**
**6+  Months**

**Influenza vaccine – ****Egg-based process and risk**

**Embryonated eggs require 6+ months from order to delivery**
**~ 1 egg is needed per each vaccine dose**
**Egg-based process limited in flexibility and reliability:**
**Chickens or embryos could be killed by virulent bird flu**
**Egg lead time hinders response to unanticipated demand, e.g. pandemic, production failures, strain changes, etc.**

**Notes:**
To do:
Double check lead and production times.
Remove production times?
Consider whether automated animation works for Rino?

## Influenza vaccine – A national priority

**	**** ****	****“****Using a cell culture approach to producing influenza vaccine offers a number of benefits.**
***	******. . . help meet surge capacity needs in the event of a shortage or pandemic . . .***
***	******. . . provide security against risks associated with egg-based production . . .***
***	******. . . provide an option for people who are allergic to eggs . . .”***

- Department of Health and Human Services, 01 Apr 05

**	****	*****“******I am asking Congress for $2.8 Billion to accelerate development of cell culture technology.”***

- President George W. Bush, 01 Nov 05

**Notes:**
To do:

Backups:
5-1 US government priority – get statements from press releases, etc. (Bill)
5-2 For US govt support, one award given, another pending (Bill)
5-3 Get HHS references for egg allergy (Bill)
5-4 Backup for question about egg allergy (TBD) – include whatever limitations there are on labeling for current products.

## Continuous cell lines – Address limitations, utilize strengths of egg process

**Use readily available raw materials**
**Involve closed-system bioreactors in place of millions of eggs **
**Allow for scalable, flexible, high volume processes**
**Are characterizable, can grow without animal-derived components**
**Used for ~30 US-licensed therapeutics + Inactivated Polio Vaccine**

**Long lead times, open handling steps**

**No lead times, closed process**

**Notes:**
To Do:
Should this have animation for the top portion?

Talking Points:
Cite Chiron in supply problems? 
Talking point for CC lines - ~30 us licensed cc biologics

Backups
6-1 Graphic for MFG process flexibility comparison – timelines (Dietmar)
6-2 Explanation of switch to cc derived seeds (Christian)
6-3 Egg process slide, including comparison of “openness”  (Ulrich/Dietmar)
6-4 Egg system cannot be pushed to cover short-term demand increases.  No rapid scalability or security (Ulrich/Dietmar)
6-5 Avian strain issue – repeat from previous
6-6 example from Netherlands flock death 2003 (David)

## Continuous cell lines –Rationale for Chiron MDCK

**Inherent characteristics:**
**Broadly and highly permissive for a wide variety of flu strains **
**Restricted growth of non-flu human pathogens that may be present in the viral seed**
**Selected characteristics:**
**Suspension adapted to provide scalable, high yield, high volume production**
**Adapted for growth in chemically defined medium (no animal-derived components)**

**Notes:**
To Do:

Talking Points:
Eliminates need for FCS and animal-derived proteins or other biologically derived materials (and thereby the risks from animal associated pathogens, e.g., FCS and the TSE agent)

Backups:
7-1 Chiron permissiveness data, strains at what scale, experience (Ulrich/Dietmar)
7-2 Suspension benefit backup (Ulrich/Dietmar)
7-3 Defined medium backup (Ulrich/Dietmar)
7-4 Restricted growth backup (Ulrich/Dietmar)

## Continuous cell lines –Advantages over primary or diploid cells

**Continuous cell lines –****Advantages over primary or diploid cells**

**1950’s****Primary**
**(Egg-based Influenza Vaccine****Measles)**

**Primary cells****Culture medium****Environment**

**1970’s****Diploid**
**(Rubella, Hepatitis A, Varicella**
**Rabies)**

**Culture medium****Environment**

**1980’s****Continuous Cell Lines**
**(IPV)**

**Environment**

**Cell Types**

**Potential sources of adventitious agent contamination**

**Poorly characterized**

**Characterized****Limited life time**

**Highly characterized****Immortal**

**Characterization of cell substrate**

**Decreased risk from adventitious agents**

**Increased characterization**

**Notes:**
To do:
Does cell type line belong in the middle, as here, or on the right?

Talking Points:
Discuss other benefits of lines

## Continuous cell lines –Potential concerns

**Continuous cell lines have the potential to be *****tumorigenic***** and/or *****oncogenic ***
**Tumorigenicity – growth of intact cells in a host animal**
**Oncogenicity – transformation of host animal cells into tumor cells**
**The potential concerns come from three sources:**

**Notes:**
To do:
Change DNA picture

Talking Points:
Cells can be passaged and selected to provide key characteristics
Passaged to grow in suspension (yield benefit)
Passaged to grow in defined medium (decreases dependence on serum)
Continued passaging has an expected, associated consequence, namely increased potential for tumorigenicity in highly immunodeficient animals

## Continuous cell lines – Regulatory approaches to risk assessment

**Testing paradigms have been defined to assess potential risk to allow safe use **
**CBER’s Points to Consider and Defined Risks Approach Algorithm (applicable to tumorigenic and non-tumorigenic cell lines)**
**ICH Guidelines**
**CHMP Guidelines**
**Chiron has applied these paradigms to safety testing of the MDCK cell line in consultation with regulatory authorities**

**Notes:**
To do:

Backups:
10-3 What regulatory requirements – ICH cell substrate, EMEA guidance, EP, Points to Consider, DRAA – list references (Maurie)

## Chiron MDCK cells – Demonstrating acceptability as a cell substrate

- Demonstrate lack of oncogenicity
- Demonstrate acceptable DNA removal and/or inactivation

- Cells

- DNA

- Adventitious Agents

- Demonstrate removal of intact cells
- Demonstrate no capacity for transformation (oncogenicity)

- Demonstrate lack of inherent agents
- Infectious
- Oncogenic
- Demonstrate removal and/or inactivation of potential agents

**Notes:**
To do:

Talking points
Explain that both in vivo and MFG assessments are part of the package

Backups:
11-1 Biologically active proteins, why not an issue if asked (Ulrich/Dietmar)
11-2 TSE/PrP backup, cat/dog story (Ulrich/David)

## Demonstrate lack of oncogenicity
Demonstrate acceptable DNA removal and/or inactivation

- Demonstrate acceptable DNA removal and/or inactivation

- Cells

- DNA

- Adventitious Agents

**Demonstrate removal of intact cells**
- Demonstrate no capacity for transformation of host cells (oncogenicity)

- Demonstrate lack of inherent agents
- Infectious
- Oncogenic
- Demonstrate removal and/or inactivation of potential agents

**Chiron MDCK cells – ****Demonstrating acceptability as a cell substrate**

**Notes:**
To do:

## Demonstrating acceptability as a cell substrate –Tumorigenicity Study

**As expected, MDCK cells were tumorigenic in nude mice**
**As few as 10 cells formed tumors**
**Therefore, assurance of cell removal during manufacturing is important**

| Group | Animals examined(N) | Histologically confirmed tumors(N) |
| --- | --- | --- |
| 101 MDCK | 24 | 3 |
| 103 MDCK | 25 | 3 |
| 105 MDCK | 24 | 10 |
| 107 MDCK | 24 | 11 |

**Notes:**
CAL fix table format

## Demonstrating acceptability as a cell substrate – Removal of intact cells

**Demonstrating acceptability as a cell substrate – Removal of intact cells**

**Chromatography**

**Addition of Detergent**
**Concentration / Diafiltration**

**ß-Propiolactone (BPL) Inactivation**

**Splitting**

**Adsorption**

**0.2 μm Filtration**

**Chromatography**

**Concentration / Diafiltration**

**Trivalent Bulk**

**0.45 μm Filtration**

**Trivalent Blending**

**0.2 μm Sterile Filtration**

**0.2 μm Filtration**

**Ultracentrifugation**

**Centrifugation**

**Most cells are lysed by influenza virus growth**
**Multiple, redundant processes designed to remove cells**
**Centrifugation**
**Filtration**
**Chemical  inactivation/disruption**
**Cells would be also removed by chromatography**

**Notes:**

Talking Points
State redundancy of filtration and chromatography

## Demonstrating acceptability as a cell substrate –Cell reduction by centrifugation

**Chromatography**

**Addition of Detergent**
**Concentration / Diafiltration**

**ß-Propiolactone (BPL) Inactivation**

**Splitting**

**Adsorption**

**0.2 μm Filtration**

**Chromatography**

**Concentration / Diafiltration**

**Trivalent Bulk**

**0.45 μm Filtration**

**Trivalent Blending**

**0.2 μm Sterile Filtration**

**0.2 μm Filtration**

**Ultracentrifugation**

**Centrifugation**

**> 2 log****10**** reduction****    (99%)**

**Disk-stack centrifuge**

**Notes:**
To do
Ulrich to provide statement for ultracentrifugation
Talking Points

## Demonstrating acceptability as a cell substrate –Cell reduction by filtration

**Chromatography**

**Addition of Detergent**
**Concentration / Diafiltration**

**ß-Propiolactone (BPL) Inactivation**

**Splitting**

**Adsorption**

**0.2 μm Filtration**

**Chromatography**

**Concentration / Diafiltration**

**Trivalent Bulk**

**0.45 μm Filtration**

**Trivalent Blending**

**0.2 μm Sterile Filtration**

**0.2 μm Filtration**

**Ultracentrifugation**

**Centrifugation**

**> 6.5 log****10**** reduction****    (99.9999%)**

**> 11.5 log****10**** reduction****    (>99.999999999%)**

**> 8.8 log****10**** reduction****    (>99.999999%)**

**> 8.8 log****10**** reduction****    (>99.999999%)**

**Notes:**
To do
Get team feedback on use of two photos at right. They are at different scale and each could drive difficult questions.  Can be modified later.

Talking Points
State redundancy of filtration and chromatography

## Demonstrating acceptability as a cell substrate – Cell reduction by chemical inactivation

**Chromatography**

**Addition of Detergent**
**Concentration / Diafiltration**

**ß-Propiolactone (BPL) Inactivation**

**Splitting**

**Adsorption**

**0.2 μm Filtration**

**Chromatography**

**Concentration / Diafiltration**

**Trivalent Bulk**

**0.45 μm Filtration**

**Trivalent Blending**

**0.2 μm Sterile Filtration**

**0.2 μm Filtration**

**Ultracentrifugation**

**Centrifugation**

**> 1 log****10**** reduction****    (90%)**

**> 1 log****10**** reduction****    (90%)**

**> 4 log****10**** reduction****    (99.99%)**

**Cells treated with splitting agent**

**Notes:**
To do

Talking Points
Explain what we are seeing in picture – all cells are dead per first and then no growth after transfer into medium

## Demonstrating acceptability as a cell substrate – Cumulative removal of intact MDCK cells

**Addition of Detergent**
**Concentration / Diafiltration**

**ß-Propiolactone (BPL) Inactivation**

**Splitting**

**Adsorption**

**0.2 μm Filtration**

**Chromatography**

**Concentration / Diafiltration**

**Trivalent Bulk**

**0.45 μm Filtration**

**Trivalent Blending**

**0.2 μm Sterile Filtration**

**0.2 μm Filtration**

**Ultracentrifugation**

**Centrifugation**

**> 4 log****10**** reduction**

**> 1 log****10**** reduction**

**> 6.5 log****10**** reduction**

**> 8.8 log****10**** reduction**

**> 8.8 log****10**** reduction**

**> 11.5 log****10**** reduction**

**> 2.0 log****10**** reduction**

**> 1 log****10**** reduction**

**> 41 log****10**** reduction = cumulative cell removal**

**Demonstrating acceptability as a cell substrate – ****Cumulative removal of intact MDCK cells**

| Theoretical starting cells/dose | 107 |
| --- | --- |
| Cumulative cell removal | 10-41 |
| Probability a single cell could be in a dose | 10-34 |

**Notes:**
To do:

Backups
17-2 To cover MFG step failure step – what is impact? (Ulrich)

## Demonstrating acceptability as a cell substrate –What does the risk of 1 cell in 1034 doses mean?

**If every person who has ever lived or will live received the vaccine each year for 100 years...**
**Then the probability of even *****one***** person receiving *****one***** MDCK cell is *****less than one in one trillion***** (1 in 10****12****)!**

| People living | ~ 6.5 x 109 (6.5 billion) |
| --- | --- |
| . . . plus people who have ever lived | ~ 1 x 1010 (10 billion) |
| . . . plus people who will live in next 5 billion years (the expected time before the sun burns out) | ~ 1020 |

**Notes:**
To do
Confirm calculations.
Would this work better with totals per line and a grand total?

Talking points
Cell risk is of unknown and potentially even no risk

Backups
18-1 on how residual risk is 1/1trillion (Bill)

## Demonstrating acceptability as a cell substrate – Summary of in vivo testing

**Program includes *****in vivo***** rodent ****studies designed in consultation with CBER**

|  | Assay |  |
| --- | --- | --- |
| Test Material
(species) | Tumorigenicity | Oncogenicity |
| Intact cells
(nude mice) | Yes
(Canine Tumors) | No
N=104 |
| Cell lysates
(neonatal nude mice, rats, and hamsters) | N/A | No
N=139 |
| Cellular DNA
(neonatal nude mice, rats, and hamsters) | N/A | No
N=224 |

**Notes:**
To do: Another version with only onco and TG conclusions
David/Team – please make sure table makes sense and is accurate

## Demonstrate lack of oncogenicity
Demonstrate acceptable DNA removal and/or inactivation

- Demonstrate acceptable DNA removal and/or inactivation

- Cells

- DNA

**Adventitious Agents**

- Demonstrate removal of intact cells
**Demonstrate no capacity for transformation of host cells (oncogenicity)**

**Demonstrate lack of inherent agents**
- Infectious
**Oncogenic**
- Demonstrate removal and/or inactivation of potential agents

**Demonstrating acceptability as a cell substrate –****Oncogenicity**

**Notes:**
To do:

## Demonstrating acceptability as a cell substrate – Oncogenicity

**Studies for oncogenicity – Cells**
**Up to 1 x 10****7**** intact MDCK cells tested in adult nude mice**
**No murine tumors observed**
**Conclusion: no oncogenicity observed**

**Notes:**
To do:

Talking Points:
This is all before any purification/inactivation takes place and nothing was seen
Make it clear that these are oncogenicity findings – TG was dealt with earlier
Reiterate TG and oncogenicity differences, recall previous slide . . .

Backup slides
20-1 Experimental design (Deborah)

## Demonstrating acceptability as a cell substrate – Oncogenicity

**Studies for oncogenicity – Lysates**
**Cell lysates from 5 x 10****6**** – 1 x 10****7**** cells in neonatal nude mice, rats and hamsters**
**No tumors observed**
**Conclusion: no oncogenicity observed**

| Treatment | Mouse(N) | Rat(N) | Hamster(N) | Total(N) |
| --- | --- | --- | --- | --- |
| MDCK | 11 | 30 | 28 | 69 |
| BPL-Flu-MDCK | 12 | 28 | 30 | 70 |
| Total | 23 | 58 | 58 | 139 |

**Notes:**
To do:

Talking Points:
This is all before any purification/inactivation takes place and nothing was seen
Make it clear that these are oncogenicity findings – TG was dealt with earlier
Reiterate TG and oncogenicity differences, recall previous slide . . .

Backup slides
20-1 Experimental design (Deborah)

## Demonstrating acceptability as a cell substrate – Oncogenicity

**Studies for oncogenicity – DNA**
**> 2800 times the dose limit of purified, high molecular weight DNA in neonatal nude mice, rats  and hamsters**
**No tumors observed**
**Conclusion: no oncogenicity observed**

| Treatment | Mouse(N) | Rat(N) | Hamster(N) | Total(N) |
| --- | --- | --- | --- | --- |
| MDCK | 4 | 29 | 30 | 63 |
| Flu-MDCK | 16 | 28 | 27 | 71 |
| BPL-Flu-MDCK | 30 | 30 | 30 | 90 |
| Total | 50 | 87 | 87 | 224 |

**Notes:**
To do:

Talking Points:
This is all before any purification/inactivation takes place and nothing was seen
Make it clear that these are oncogenicity findings – TG was dealt with earlier
Reiterate TG and oncogenicity differences, recall previous slide . . .

Backup slides
20-1 Experimental design (Deborah)

## Demonstrating acceptability as a cell substrate – Production process removes and degrades DNA

**< 10ng DNA/dose (as recommended by WHO for continuous cell lines)**
**Remaining DNA is**
**Degraded to < 200 base pairs primarily by ****ß****-propiolactone treatment (typical oncogenes are >1000 base pairs)**
**Inactivated by ****ß****-propiolactone treatment**
**Analysis for canine genes by PCR at the end of production – none found**

- Intact DNA

**BPL Treatment**

**Notes:**
To do:
Double check accuracy of language for 10ng reference

Talking Points
No oncogenicity before the process and even lower risk after process
PCR finally confirms that nothing got through

Backups
21-1 BPL treatment backup slide(s) (Ulrich/Dietmar)
21-2 More discussion of 200 BP – size distribution, etc. (Ulrich/Dietmar)
21-3 Oncogene size reference (David)
21-4 Level of DNA and why our situation is safe and reasonable (David)
21-5 Genes tested for by PCR (Ulrich/Dietmar)
21-6 What is actual DNA level lot-to-lot? (Ulrich)

## Demonstrating acceptability as a cell substrate – Adventitious agents

- Demonstrate lack of oncogenicity
- Demonstrate acceptable DNA removal and/or inactivation

- Cells

- DNA

- Adventitious Agents

- Demonstrate removal of intact cells
- Demonstrate no capacity for transformation (oncogenicity)

**Demonstrate lack of inherent agents**
**Infectious**
**Oncogenic**
**Demonstrate removal and/or inactivation of potential agents**

## Demonstrating acceptability as a cell substrate – Viral testing of MDCK cells

**Viruses could be introduced from multiple sources during cell line development**
**Testing was performed in**
**Pre-cell bank**
**Master cell bank**
**Working cell bank**
**End of production cells**

**Notes:**
To do:

Talking point
We have studied which viruses will grow in our MDCK and test for those viruses to protect against inadvertent introduction via seed (?)
Comment on possible sources

Backup Slides
23-1 Sources of viruses during cell line development (Ulrich)

## Demonstrating acceptability as a cell substrate – Viral testing of MDCK cells

**Broad screening assays used for virus families**
**Electron microscopy**
***In vitro***** infectivity using indicator cell lines**
***In vivo***** assays**
**Reverse transcriptase for retroviruses**
**Specific and non-specific assays used for individual viruses**
**Animal viruses (canine, bovine, porcine, equine, murine)**
**Human viruses**
**All tests negative**

**Notes:**
To do:

Talking point
We have studied which viruses will grow in our MDCK and test for those viruses to protect against inadvertent introduction via seed (?)
Comment on possible sources

Backup Slides
24-1 Specific and broad screening assay detail slides (Ulrich/Dietmar)
24-2 Non-cell line testing for AAs in product (Deborah/Dietmar)

## Demonstrating acceptability as a cell substrate – Testing for latent adventitious agents

**Redundant PCR assays for herpesviruses and polyomaviruses conducted**
**Negative (report not yet submitted to CBER)**
**Induction assays for latent viruses**
**Protocol in development**

**Notes:**
To do:

Talking point
We have studied which viruses will grow in our MDCK and test for those viruses to protect against inadvertent introduction via seed (?)
Comment on possible sources

Backup Slides
24-1 Specific and broad screening assay detail slides (Ulrich/Dietmar)
24-2 Non-cell line testing for AAs in product (Deborah/Dietmar)

## Demonstrating acceptability as a cell substrate – Removal of potential contaminating viruses 

**Demonstrating acceptability as a cell substrate – ****Removal of potential contaminating viruses **

**Chromatography**

**Addition of Detergent**
**Concentration / Diafiltration**

**ß-Propiolactone (BPL) Inactivation**

**Splitting**

**Adsorption**

**0.2 μm Filtration**

**Chromatography**

**Concentration / Diafiltration**

**Trivalent Bulk**

**0.45 μm Filtration**

**Trivalent Blending**

**0.2 μm Sterile Filtration**

**0.2 μm Filtration**

**Ultracentrifugation**

**Centrifugation**

**Viruses may be introduced during processing – from virus seed, environment, etc.**
**Multiple processes designed to remove these viral agents, thus providing an additional margin of safety**
**Inactivation by ß-propiolactone**
**Splitting**
**Ultracentrifugation**
**Adsorption**

**Notes:**
To do:

Talking Points:
Reiterate that we have shown cells, etc to be free and this addresses potential contamination as well as occult agents

## Demonstrating acceptability as a cell substrate – Viral reduction by process

- (Selection criteria: enveloped, non-enveloped, RNA, DNA, single-stranded, double stranded, BPL-resistant)

**Demonstrating acceptability as a cell substrate – ****Viral reduction by process**

**Chromatography**

**Addition of Detergent**
**Concentration / Diafiltration**

**ß-Propiolactone (BPL) Inactivation**

**Splitting**

**Adsorption**

**0.2 μm Filtration**

**Chromatography**

**Concentration / Diafiltration**

**Trivalent Bulk**

**0.45 μm Filtration**

**Trivalent Blending**

**0.2 μm Sterile Filtration**

**0.2 μm Filtration**

**Ultracentrifugation**

**Centrifugation**

|  | Herpes simplex virus
(ds-DNA, enveloped) | Reovirus 3
(ds-RNA, non-enveloped) | Murine Retrovirus
(ss-RNA, enveloped) |  |
| --- | --- | --- | --- | --- |
| BPL inactivation | 4.5 log10 | 2.3 log10 |  4.5 log10 |  |
| SplittingUltra-centrifugationAdsorption |  5.5 log10 |  7.6 log10 |  7.6 log10 |  |
| Combined virus reduction |  10 log10 |  9.9 log10 |  12.1 log10 |  |

**Virus removal was >9.9 log****10**** for all challenges**

**Notes:**
To do:

Talking Points:
Reiterate that we have shown cells, etc to be free and this addresses potential contamination as well as occult agents

Backups:
26-1 validation/status of reduction numbers from process (Ulrich/Dietmar)

## MDCK cell line and manufacturing summary

**MDCK Cell Line**
**Intact MDCK cells are tumorigenic**
**No oncogenicity observed in cell, lysate and DNA studies**
**No adventitious agents detected**
**Process**
**Removes intact cells**
**DNA reduced to <10ng/dose**
**Residual DNA inactivated**
**Potential adventitious agents removed and/or inactivated**

## Status of clinical development of cell-derived influenza vaccine

**European Union activities**
**Phase 1, 2 and 3 studies carried out in Europe**
**> 3000 subjects received vaccine since 2002**
**Tolerability and immunogenicity comparable to a licensed egg-derived subunit vaccine**
**US activities**
**Phase 1/2 US study underway**
**Enrollment complete**

## Overall summary

**There is an unmet public need for a readily available and reliable supply of flu vaccine. **
**Chiron has developed a robust, scalable and safe manufacturing process, which utilizes MDCK cells to meet this need.**

**Conclusion Image**

## Influenza vaccine – A national priority

**In reference to the influenza vaccine:**
**“****The Cell-based technology . . . will change the world of vaccine production forever”**

- Michael Leavitt, Secretary, Health and Human Services, 27 Oct 05

**Notes:**
Is the photo gratuitous?