Topical and Transdermal Community

We are moving into P3 clinical trials with a hydrogel-based product intended for topical derm application to perturbed (burned) skin. At our last Agency briefing they positioned that the product needs to be sterile. The drug product as formulated is a low bioburden, non-sterile, preserved aqueous gel packaged in a multi-dose container. There are many examples of comparable drug products currently approved for application to compromised skin that share a similar formulation and packaging characteristics yet are not sterile. Further, this product will be packaged in 120g tubes, and I am unaware of any CMO that offers sterile fill/finish for this package size. 

Any guidance from the Community on navigating this regulatory challenge would be most appreciated. 

------------------------------
Robert Butler
VP, CMC & Process Development
Xequel Bio, Inc.
Fort Worth TX
[email protected]

Disclaimer: Opinions expressed are solely my own and do not express the views or opinions of my employer.
------------------------------

To: Robert Butler
VP, CMC & Process Development
Xequel Bio, Inc.
Fort Worth TX

This is quite unusual for a Topical Dermatological Drug Product of low bioburden. However, for the burned (perturbed) skin the agency may be asking for extra pre-caution to be sterile. This is due to the fact that your drug product is hydrogel based. Which means it is hydrophilic, i.e., has got water prone to microbial growth. I hope you have done for the release test of the semi-solid drug product the following:

Release Tests for Semi-Solid Drug products

·         In-house more tighter for the release than stability specifications for assay and impurity

·         Compendial: Wherever they are appropriate, pharmacopeial procedures (testing and acceptance criteria) should be utilized

·         Identification: for the drug substance

·         Visual test for homogeneity of drug product

·         pH, viscosity, specific gravity

·         Antioxidant content.

·         Microbial test: microbiological examination of

·         Non -sterile products, for., USP <61>, <62>, and <111.

Manufacturing is compliant with USP <87>, USP <88> and conforms to 21 CFR 177 and 178.      

I would say if you have at least some Aseptic Manufacturing process for this product to ensure that the product would be safe from therapeutic and biologic point. 

Some suggested SOPs for such type of product Manufacturing:

Personal Hygiene Procedures and Requirements for Non-sterile Process Area:

In Locker Room: Change from personal clothes, shoes and other personal wares to the following: 

Protective Uniforms: Non-sterile clean, single or two-piece, white (other light color) uniforms without pockets made from lint-free weave, e.g. polyester/cotton (67/33).

Footwear: Non-sterile special/separate white snickers/clogs and worn at all times within the area. 

Head Gear: Non-sterile disposable headgear totally enclosing hair and facial hair

Face Mask: Non-sterile, non-linting face mask be worn before entering Personnel Air Lock.

After use face mask must be disposed of in a waste bin placed in the outer part of the air lock.

Hygiene of the Hands: The hands must be well-tended. No open lesions shall be discernable. Small lesions/infections must be thoroughly covered with a Band-Aid or bandage. The nails must be clean and cut. Nail polish or other cosmetics which can shed particles must not be used.  Hands must be thoroughly washed and disinfected before entering the Manufacturing Area, before starting a work operation or when the hands have become dirty. Disposable gloves must be worn within the areas intended for the preparation of drug products. The gloves must be changed prior to each working operation. Damaged gloves must be exchanged immediately. Used gloves must be disposed of in a waste bin placed in the outer part of the air lock.

Protective Uniforms: One-piece, light color uniforms gathered at the wrists and ankle and provided with a high neck without pockets made from lint-free, non-particle shedding materials (100% polyester).

For terminal sterilized production area sterilized uniforms must be changed at least every day. For the aseptic filling area the sterilized garments must be changed at every entry.

Footwear: When entering the Manufacturing Area personal shoes must be changed to specially designated shoe preferably of another color for distinction.   The shoe must be clean and when not used, kept at a fixed place within the inner part of the air lock. In addition, clean socks shall be worn totally enclosing the feet and with the trouser bottom tucked inside the socks.

Head Gear: Lint-free, non-particle shedding must totally enclose hair/beard and worn tucked inside the neck of the uniform

Face Mask: A non-lint face mask be worn covering nose and mouth to prevent shedding droplets. Touching the face mask must be avoided. If so, the hand must be thoroughly disinfected. After use face mask must be disposed of in a waste bin.

P.S:  In the past when I was a Senior CMC reviewer at FDA/CDER/OPQ/OPMA have given the following deficiency for a Solid Drug product > 50% Lactose prone/susceptible to microbial growth.

"The formulation for your drug product contains >50% Lactose, which makes it susceptible to microbial growth. Thus, we request that you include microbial controls for the release and stability of your product. Alternatively, you may conduct a onetime test for water activity (a_w) of the finished product and provide us with the data or demonstrate by a suitable method that your formulation does not support microbial growth."

If you have taken care all these points that I have cited then I am sure you can give a response that your drug product should not require to be sterile.

I hope I was able to give some answer to your question and suggestions.

Thanks.

Masih Jaigirdar

We are moving into P3 clinical trials with a hydrogel-based product intended for topical derm application to perturbed (burned) skin. At our last Agency briefing they positioned that the product needs to be sterile. The drug product as formulated is a low bioburden, non-sterile, preserved aqueous gel packaged in a multi-dose container. There are many examples of comparable drug products currently approved for application to compromised skin that share a similar formulation and packaging characteristics yet are not sterile. Further, this product will be packaged in 120g tubes, and I am unaware of any CMO that offers sterile fill/finish for this package size. 

Any guidance from the Community on navigating this regulatory challenge would be most appreciated. 

To: Robert Butler
VP, CMC & Process Development
Xequel Bio, Inc.
Fort Worth TX

This is quite unusual for a Topical Dermatological Drug Product of low bioburden. However, for the burned (perturbed) skin the agency may be asking for extra pre-caution to be sterile. This is due to the fact that your drug product is hydrogel based. Which means it is hydrophilic, i.e., has got water prone to microbial growth. I hope you have done for the release test of the semi-solid drug product the following:

Release Tests for Semi-Solid Drug products

·         In-house more tighter for the release than stability specifications for assay and impurity

·         Compendial: Wherever they are appropriate, pharmacopeial procedures (testing and acceptance criteria) should be utilized

·         Identification: for the drug substance

·         Visual test for homogeneity of drug product

·         pH, viscosity, specific gravity

·         Antioxidant content.

·         Microbial test: microbiological examination of

·         Non -sterile products, for., USP <61>, <62>, and <111.

Manufacturing is compliant with USP <87>, USP <88> and conforms to 21 CFR 177 and 178.      

I would say if you have at least some Aseptic Manufacturing process for this product to ensure that the product would be safe from therapeutic and biologic point. 

Some suggested SOPs for such type of product Manufacturing:

Personal Hygiene Procedures and Requirements for Non-sterile Process Area:

In Locker Room: Change from personal clothes, shoes and other personal wares to the following: 

Protective Uniforms: Non-sterile clean, single or two-piece, white (other light color) uniforms without pockets made from lint-free weave, e.g. polyester/cotton (67/33).

Footwear: Non-sterile special/separate white snickers/clogs and worn at all times within the area. 

Head Gear: Non-sterile disposable headgear totally enclosing hair and facial hair

Face Mask: Non-sterile, non-linting face mask be worn before entering Personnel Air Lock.

After use face mask must be disposed of in a waste bin placed in the outer part of the air lock.

Hygiene of the Hands: The hands must be well-tended. No open lesions shall be discernable. Small lesions/infections must be thoroughly covered with a Band-Aid or bandage. The nails must be clean and cut. Nail polish or other cosmetics which can shed particles must not be used.  Hands must be thoroughly washed and disinfected before entering the Manufacturing Area, before starting a work operation or when the hands have become dirty. Disposable gloves must be worn within the areas intended for the preparation of drug products. The gloves must be changed prior to each working operation. Damaged gloves must be exchanged immediately. Used gloves must be disposed of in a waste bin placed in the outer part of the air lock.

Protective Uniforms: One-piece, light color uniforms gathered at the wrists and ankle and provided with a high neck without pockets made from lint-free, non-particle shedding materials (100% polyester).

For terminal sterilized production area sterilized uniforms must be changed at least every day. For the aseptic filling area the sterilized garments must be changed at every entry.

Footwear: When entering the Manufacturing Area personal shoes must be changed to specially designated shoe preferably of another color for distinction.   The shoe must be clean and when not used, kept at a fixed place within the inner part of the air lock. In addition, clean socks shall be worn totally enclosing the feet and with the trouser bottom tucked inside the socks.

Head Gear: Lint-free, non-particle shedding must totally enclose hair/beard and worn tucked inside the neck of the uniform

Face Mask: A non-lint face mask be worn covering nose and mouth to prevent shedding droplets. Touching the face mask must be avoided. If so, the hand must be thoroughly disinfected. After use face mask must be disposed of in a waste bin.

P.S:  In the past when I was a Senior CMC reviewer at FDA/CDER/OPQ/OPMA have given the following deficiency for a Solid Drug product > 50% Lactose prone/susceptible to microbial growth.

"The formulation for your drug product contains >50% Lactose, which makes it susceptible to microbial growth. Thus, we request that you include microbial controls for the release and stability of your product. Alternatively, you may conduct a onetime test for water activity (a_w) of the finished product and provide us with the data or demonstrate by a suitable method that your formulation does not support microbial growth."

If you have taken care all these points that I have cited then I am sure you can give a response that your drug product should not require to be sterile.

I hope I was able to give some answer to your question and suggestions.

Thanks.

Masih Jaigirdar

We are moving into P3 clinical trials with a hydrogel-based product intended for topical derm application to perturbed (burned) skin. At our last Agency briefing they positioned that the product needs to be sterile. The drug product as formulated is a low bioburden, non-sterile, preserved aqueous gel packaged in a multi-dose container. There are many examples of comparable drug products currently approved for application to compromised skin that share a similar formulation and packaging characteristics yet are not sterile. Further, this product will be packaged in 120g tubes, and I am unaware of any CMO that offers sterile fill/finish for this package size. 

Any guidance from the Community on navigating this regulatory challenge would be most appreciated. 

Dear Robert,

My suggestion would be you can also conduct a onetime test for water activity (a_w) of the finished product and provide them with the data or demonstrate by a suitable method that your formulation does not support microbial growth. This should suffice their asking for making the product sterile. 

With best wishes.

Thanks.

Masih

To: Robert Butler
VP, CMC & Process Development
Xequel Bio, Inc.
Fort Worth TX

This is quite unusual for a Topical Dermatological Drug Product of low bioburden. However, for the burned (perturbed) skin the agency may be asking for extra pre-caution to be sterile. This is due to the fact that your drug product is hydrogel based. Which means it is hydrophilic, i.e., has got water prone to microbial growth. I hope you have done for the release test of the semi-solid drug product the following:

Release Tests for Semi-Solid Drug products

·         In-house more tighter for the release than stability specifications for assay and impurity

·         Compendial: Wherever they are appropriate, pharmacopeial procedures (testing and acceptance criteria) should be utilized

·         Identification: for the drug substance

·         Visual test for homogeneity of drug product

·         pH, viscosity, specific gravity

·         Antioxidant content.

·         Microbial test: microbiological examination of

·         Non -sterile products, for., USP <61>, <62>, and <111.

Manufacturing is compliant with USP <87>, USP <88> and conforms to 21 CFR 177 and 178.      

I would say if you have at least some Aseptic Manufacturing process for this product to ensure that the product would be safe from therapeutic and biologic point. 

Some suggested SOPs for such type of product Manufacturing:

Personal Hygiene Procedures and Requirements for Non-sterile Process Area:

In Locker Room: Change from personal clothes, shoes and other personal wares to the following: 

Protective Uniforms: Non-sterile clean, single or two-piece, white (other light color) uniforms without pockets made from lint-free weave, e.g. polyester/cotton (67/33).

Footwear: Non-sterile special/separate white snickers/clogs and worn at all times within the area. 

Head Gear: Non-sterile disposable headgear totally enclosing hair and facial hair

Face Mask: Non-sterile, non-linting face mask be worn before entering Personnel Air Lock.

After use face mask must be disposed of in a waste bin placed in the outer part of the air lock.

Hygiene of the Hands: The hands must be well-tended. No open lesions shall be discernable. Small lesions/infections must be thoroughly covered with a Band-Aid or bandage. The nails must be clean and cut. Nail polish or other cosmetics which can shed particles must not be used.  Hands must be thoroughly washed and disinfected before entering the Manufacturing Area, before starting a work operation or when the hands have become dirty. Disposable gloves must be worn within the areas intended for the preparation of drug products. The gloves must be changed prior to each working operation. Damaged gloves must be exchanged immediately. Used gloves must be disposed of in a waste bin placed in the outer part of the air lock.

Protective Uniforms: One-piece, light color uniforms gathered at the wrists and ankle and provided with a high neck without pockets made from lint-free, non-particle shedding materials (100% polyester).

For terminal sterilized production area sterilized uniforms must be changed at least every day. For the aseptic filling area the sterilized garments must be changed at every entry.

Footwear: When entering the Manufacturing Area personal shoes must be changed to specially designated shoe preferably of another color for distinction.   The shoe must be clean and when not used, kept at a fixed place within the inner part of the air lock. In addition, clean socks shall be worn totally enclosing the feet and with the trouser bottom tucked inside the socks.

Head Gear: Lint-free, non-particle shedding must totally enclose hair/beard and worn tucked inside the neck of the uniform

Face Mask: A non-lint face mask be worn covering nose and mouth to prevent shedding droplets. Touching the face mask must be avoided. If so, the hand must be thoroughly disinfected. After use face mask must be disposed of in a waste bin.

P.S:  In the past when I was a Senior CMC reviewer at FDA/CDER/OPQ/OPMA have given the following deficiency for a Solid Drug product > 50% Lactose prone/susceptible to microbial growth.

"The formulation for your drug product contains >50% Lactose, which makes it susceptible to microbial growth. Thus, we request that you include microbial controls for the release and stability of your product. Alternatively, you may conduct a onetime test for water activity (a_w) of the finished product and provide us with the data or demonstrate by a suitable method that your formulation does not support microbial growth."

If you have taken care all these points that I have cited then I am sure you can give a response that your drug product should not require to be sterile.

I hope I was able to give some answer to your question and suggestions.

Thanks.

Masih Jaigirdar

------------------------------
Masihuddin Jaigirdar
Pharmaceutics Expert (FDA & Industry Sector)
MJ Consultant
Silver Spring MD
[email protected]

Disclaimer: Opinions expressed are solely my own and do not express the views or opinions of my employer.MasihuddinMasihuddinMasihuddinMasihuddin

Original Message:
Sent: 10-25-2023 14:58
From: Robert Butler
Subject: Sterile Topical Derm Products - Regulatory Guidance

We are moving into P3 clinical trials with a hydrogel-based product intended for topical derm application to perturbed (burned) skin. At our last Agency briefing they positioned that the product needs to be sterile. The drug product as formulated is a low bioburden, non-sterile, preserved aqueous gel packaged in a multi-dose container. There are many examples of comparable drug products currently approved for application to compromised skin that share a similar formulation and packaging characteristics yet are not sterile. Further, this product will be packaged in 120g tubes, and I am unaware of any CMO that offers sterile fill/finish for this package size. 

Any guidance from the Community on navigating this regulatory challenge would be most appreciated. 

Dear Robert,

My suggestion would be you can also conduct a onetime test for water activity (a_w) of the finished product and provide them with the data or demonstrate by a suitable method that your formulation does not support microbial growth. This should suffice their asking for making the product sterile. 

With best wishes.

Thanks.

Masih

To: Robert Butler
VP, CMC & Process Development
Xequel Bio, Inc.
Fort Worth TX

This is quite unusual for a Topical Dermatological Drug Product of low bioburden. However, for the burned (perturbed) skin the agency may be asking for extra pre-caution to be sterile. This is due to the fact that your drug product is hydrogel based. Which means it is hydrophilic, i.e., has got water prone to microbial growth. I hope you have done for the release test of the semi-solid drug product the following:

Release Tests for Semi-Solid Drug products

·         In-house more tighter for the release than stability specifications for assay and impurity

·         Compendial: Wherever they are appropriate, pharmacopeial procedures (testing and acceptance criteria) should be utilized

·         Identification: for the drug substance

·         Visual test for homogeneity of drug product

·         pH, viscosity, specific gravity

·         Antioxidant content.

·         Microbial test: microbiological examination of

·         Non -sterile products, for., USP <61>, <62>, and <111.

Manufacturing is compliant with USP <87>, USP <88> and conforms to 21 CFR 177 and 178.      

I would say if you have at least some Aseptic Manufacturing process for this product to ensure that the product would be safe from therapeutic and biologic point. 

Some suggested SOPs for such type of product Manufacturing:

Personal Hygiene Procedures and Requirements for Non-sterile Process Area:

In Locker Room: Change from personal clothes, shoes and other personal wares to the following: 

Protective Uniforms: Non-sterile clean, single or two-piece, white (other light color) uniforms without pockets made from lint-free weave, e.g. polyester/cotton (67/33).

Footwear: Non-sterile special/separate white snickers/clogs and worn at all times within the area. 

Head Gear: Non-sterile disposable headgear totally enclosing hair and facial hair

Face Mask: Non-sterile, non-linting face mask be worn before entering Personnel Air Lock.

After use face mask must be disposed of in a waste bin placed in the outer part of the air lock.

Hygiene of the Hands: The hands must be well-tended. No open lesions shall be discernable. Small lesions/infections must be thoroughly covered with a Band-Aid or bandage. The nails must be clean and cut. Nail polish or other cosmetics which can shed particles must not be used.  Hands must be thoroughly washed and disinfected before entering the Manufacturing Area, before starting a work operation or when the hands have become dirty. Disposable gloves must be worn within the areas intended for the preparation of drug products. The gloves must be changed prior to each working operation. Damaged gloves must be exchanged immediately. Used gloves must be disposed of in a waste bin placed in the outer part of the air lock.

Protective Uniforms: One-piece, light color uniforms gathered at the wrists and ankle and provided with a high neck without pockets made from lint-free, non-particle shedding materials (100% polyester).

For terminal sterilized production area sterilized uniforms must be changed at least every day. For the aseptic filling area the sterilized garments must be changed at every entry.

Footwear: When entering the Manufacturing Area personal shoes must be changed to specially designated shoe preferably of another color for distinction.   The shoe must be clean and when not used, kept at a fixed place within the inner part of the air lock. In addition, clean socks shall be worn totally enclosing the feet and with the trouser bottom tucked inside the socks.

Head Gear: Lint-free, non-particle shedding must totally enclose hair/beard and worn tucked inside the neck of the uniform

Face Mask: A non-lint face mask be worn covering nose and mouth to prevent shedding droplets. Touching the face mask must be avoided. If so, the hand must be thoroughly disinfected. After use face mask must be disposed of in a waste bin.

P.S:  In the past when I was a Senior CMC reviewer at FDA/CDER/OPQ/OPMA have given the following deficiency for a Solid Drug product > 50% Lactose prone/susceptible to microbial growth.

"The formulation for your drug product contains >50% Lactose, which makes it susceptible to microbial growth. Thus, we request that you include microbial controls for the release and stability of your product. Alternatively, you may conduct a onetime test for water activity (a_w) of the finished product and provide us with the data or demonstrate by a suitable method that your formulation does not support microbial growth."

If you have taken care all these points that I have cited then I am sure you can give a response that your drug product should not require to be sterile.

I hope I was able to give some answer to your question and suggestions.

Thanks.

Masih Jaigirdar

------------------------------
Masihuddin Jaigirdar
Pharmaceutics Expert (FDA & Industry Sector)
MJ Consultant
Silver Spring MD
[email protected]

Disclaimer: Opinions expressed are solely my own and do not express the views or opinions of my employer.MasihuddinMasihuddinMasihuddinMasihuddin

Original Message:
Sent: 10-25-2023 14:58
From: Robert Butler
Subject: Sterile Topical Derm Products - Regulatory Guidance

We are moving into P3 clinical trials with a hydrogel-based product intended for topical derm application to perturbed (burned) skin. At our last Agency briefing they positioned that the product needs to be sterile. The drug product as formulated is a low bioburden, non-sterile, preserved aqueous gel packaged in a multi-dose container. There are many examples of comparable drug products currently approved for application to compromised skin that share a similar formulation and packaging characteristics yet are not sterile. Further, this product will be packaged in 120g tubes, and I am unaware of any CMO that offers sterile fill/finish for this package size. 

Any guidance from the Community on navigating this regulatory challenge would be most appreciated. 

Using low activity to justify a non-sterile topically administered product to non-intact skin will be difficult to justify to FDA, especially to the clinical reviewers in the Derm division.  This is compounded by having a product formulated using hydrogels.

David

------------------------------
David Lin Ph.D.
President
TS PHARMA EXPERTS LLC
Potomac MD
[email protected]

Disclaimer: Opinions expressed are solely my own and do not express the views or opinions of my employer.

Original Message:
Sent: 10-31-2023 12:12
From: Masihuddin Jaigirdar
Subject: Sterile Topical Derm Products - Regulatory Guidance

Dear Robert,

My suggestion would be you can also conduct a onetime test for water activity (a_w) of the finished product and provide them with the data or demonstrate by a suitable method that your formulation does not support microbial growth. This should suffice their asking for making the product sterile. 

With best wishes.

Thanks.

Masih

------------------------------
Masihuddin Jaigirdar
Pharmaceutics Expert (FDA & Industry Sector)
MJ Consultant
Silver Spring MD
[email protected]

Disclaimer: Opinions expressed are solely my own and do not express the views or opinions of my employer.MasihuddinMasihuddinMasihuddinMasihuddin

Original Message:
Sent: 10-31-2023 10:22
From: Robert Butler
Subject: Sterile Topical Derm Products - Regulatory Guidance

Original Message:
Sent: 10/31/2023 10:13:00 AM
From: Masihuddin Jaigirdar
Subject: RE: Sterile Topical Derm Products - Regulatory Guidance

To: Robert Butler
VP, CMC & Process Development
Xequel Bio, Inc.
Fort Worth TX

This is quite unusual for a Topical Dermatological Drug Product of low bioburden. However, for the burned (perturbed) skin the agency may be asking for extra pre-caution to be sterile. This is due to the fact that your drug product is hydrogel based. Which means it is hydrophilic, i.e., has got water prone to microbial growth. I hope you have done for the release test of the semi-solid drug product the following:

Release Tests for Semi-Solid Drug products

·         In-house more tighter for the release than stability specifications for assay and impurity

·         Compendial: Wherever they are appropriate, pharmacopeial procedures (testing and acceptance criteria) should be utilized

·         Identification: for the drug substance

·         Visual test for homogeneity of drug product

·         pH, viscosity, specific gravity

·         Antioxidant content.

·         Microbial test: microbiological examination of

·         Non -sterile products, for., USP <61>, <62>, and <111.

Manufacturing is compliant with USP <87>, USP <88> and conforms to 21 CFR 177 and 178.      

I would say if you have at least some Aseptic Manufacturing process for this product to ensure that the product would be safe from therapeutic and biologic point. 

Some suggested SOPs for such type of product Manufacturing:

Personal Hygiene Procedures and Requirements for Non-sterile Process Area:

In Locker Room: Change from personal clothes, shoes and other personal wares to the following: 

Protective Uniforms: Non-sterile clean, single or two-piece, white (other light color) uniforms without pockets made from lint-free weave, e.g. polyester/cotton (67/33).

Footwear: Non-sterile special/separate white snickers/clogs and worn at all times within the area. 

Head Gear: Non-sterile disposable headgear totally enclosing hair and facial hair

Face Mask: Non-sterile, non-linting face mask be worn before entering Personnel Air Lock.

After use face mask must be disposed of in a waste bin placed in the outer part of the air lock.

Hygiene of the Hands: The hands must be well-tended. No open lesions shall be discernable. Small lesions/infections must be thoroughly covered with a Band-Aid or bandage. The nails must be clean and cut. Nail polish or other cosmetics which can shed particles must not be used.  Hands must be thoroughly washed and disinfected before entering the Manufacturing Area, before starting a work operation or when the hands have become dirty. Disposable gloves must be worn within the areas intended for the preparation of drug products. The gloves must be changed prior to each working operation. Damaged gloves must be exchanged immediately. Used gloves must be disposed of in a waste bin placed in the outer part of the air lock.

Protective Uniforms: One-piece, light color uniforms gathered at the wrists and ankle and provided with a high neck without pockets made from lint-free, non-particle shedding materials (100% polyester).

For terminal sterilized production area sterilized uniforms must be changed at least every day. For the aseptic filling area the sterilized garments must be changed at every entry.

Footwear: When entering the Manufacturing Area personal shoes must be changed to specially designated shoe preferably of another color for distinction.   The shoe must be clean and when not used, kept at a fixed place within the inner part of the air lock. In addition, clean socks shall be worn totally enclosing the feet and with the trouser bottom tucked inside the socks.

Head Gear: Lint-free, non-particle shedding must totally enclose hair/beard and worn tucked inside the neck of the uniform

Face Mask: A non-lint face mask be worn covering nose and mouth to prevent shedding droplets. Touching the face mask must be avoided. If so, the hand must be thoroughly disinfected. After use face mask must be disposed of in a waste bin.

P.S:  In the past when I was a Senior CMC reviewer at FDA/CDER/OPQ/OPMA have given the following deficiency for a Solid Drug product > 50% Lactose prone/susceptible to microbial growth.

"The formulation for your drug product contains >50% Lactose, which makes it susceptible to microbial growth. Thus, we request that you include microbial controls for the release and stability of your product. Alternatively, you may conduct a onetime test for water activity (a_w) of the finished product and provide us with the data or demonstrate by a suitable method that your formulation does not support microbial growth."

If you have taken care all these points that I have cited then I am sure you can give a response that your drug product should not require to be sterile.

I hope I was able to give some answer to your question and suggestions.

Thanks.

Masih Jaigirdar

------------------------------
Masihuddin Jaigirdar
Pharmaceutics Expert (FDA & Industry Sector)
MJ Consultant
Silver Spring MD
[email protected]

Disclaimer: Opinions expressed are solely my own and do not express the views or opinions of my employer.MasihuddinMasihuddinMasihuddinMasihuddin

Original Message:
Sent: 10-25-2023 14:58
From: Robert Butler
Subject: Sterile Topical Derm Products - Regulatory Guidance

We are moving into P3 clinical trials with a hydrogel-based product intended for topical derm application to perturbed (burned) skin. At our last Agency briefing they positioned that the product needs to be sterile. The drug product as formulated is a low bioburden, non-sterile, preserved aqueous gel packaged in a multi-dose container. There are many examples of comparable drug products currently approved for application to compromised skin that share a similar formulation and packaging characteristics yet are not sterile. Further, this product will be packaged in 120g tubes, and I am unaware of any CMO that offers sterile fill/finish for this package size. 

Any guidance from the Community on navigating this regulatory challenge would be most appreciated. 

------------------------------
Robert Butler
VP, CMC & Process Development
Xequel Bio, Inc.
Fort Worth TX
[email protected]

Disclaimer: Opinions expressed are solely my own and do not express the views or opinions of my employer.
------------------------------

To: Robert Butler
VP, CMC & Process Development
Xequel Bio, Inc.
Fort Worth TX

This is quite unusual for a Topical Dermatological Drug Product of low bioburden. However, for the burned (perturbed) skin the agency may be asking for extra pre-caution to be sterile. This is due to the fact that your drug product is hydrogel based. Which means it is hydrophilic, i.e., has got water prone to microbial growth. I hope you have done for the release test of the semi-solid drug product the following:

Release Tests for Semi-Solid Drug products

·         In-house more tighter for the release than stability specifications for assay and impurity

·         Compendial: Wherever they are appropriate, pharmacopeial procedures (testing and acceptance criteria) should be utilized

·         Identification: for the drug substance

·         Visual test for homogeneity of drug product

·         pH, viscosity, specific gravity

·         Antioxidant content.

·         Microbial test: microbiological examination of

·         Non -sterile products, for., USP <61>, <62>, and <111.

Manufacturing is compliant with USP <87>, USP <88> and conforms to 21 CFR 177 and 178.      

I would say if you have at least some Aseptic Manufacturing process for this product to ensure that the product would be safe from therapeutic and biologic point. 

Some suggested SOPs for such type of product Manufacturing:

Personal Hygiene Procedures and Requirements for Non-sterile Process Area:

In Locker Room: Change from personal clothes, shoes and other personal wares to the following: 

Protective Uniforms: Non-sterile clean, single or two-piece, white (other light color) uniforms without pockets made from lint-free weave, e.g. polyester/cotton (67/33).

Footwear: Non-sterile special/separate white snickers/clogs and worn at all times within the area. 

Head Gear: Non-sterile disposable headgear totally enclosing hair and facial hair

Face Mask: Non-sterile, non-linting face mask be worn before entering Personnel Air Lock.

After use face mask must be disposed of in a waste bin placed in the outer part of the air lock.

Hygiene of the Hands: The hands must be well-tended. No open lesions shall be discernable. Small lesions/infections must be thoroughly covered with a Band-Aid or bandage. The nails must be clean and cut. Nail polish or other cosmetics which can shed particles must not be used.  Hands must be thoroughly washed and disinfected before entering the Manufacturing Area, before starting a work operation or when the hands have become dirty. Disposable gloves must be worn within the areas intended for the preparation of drug products. The gloves must be changed prior to each working operation. Damaged gloves must be exchanged immediately. Used gloves must be disposed of in a waste bin placed in the outer part of the air lock.

Protective Uniforms: One-piece, light color uniforms gathered at the wrists and ankle and provided with a high neck without pockets made from lint-free, non-particle shedding materials (100% polyester).

For terminal sterilized production area sterilized uniforms must be changed at least every day. For the aseptic filling area the sterilized garments must be changed at every entry.

Footwear: When entering the Manufacturing Area personal shoes must be changed to specially designated shoe preferably of another color for distinction.   The shoe must be clean and when not used, kept at a fixed place within the inner part of the air lock. In addition, clean socks shall be worn totally enclosing the feet and with the trouser bottom tucked inside the socks.

Head Gear: Lint-free, non-particle shedding must totally enclose hair/beard and worn tucked inside the neck of the uniform

Face Mask: A non-lint face mask be worn covering nose and mouth to prevent shedding droplets. Touching the face mask must be avoided. If so, the hand must be thoroughly disinfected. After use face mask must be disposed of in a waste bin.

P.S:  In the past when I was a Senior CMC reviewer at FDA/CDER/OPQ/OPMA have given the following deficiency for a Solid Drug product > 50% Lactose prone/susceptible to microbial growth.

"The formulation for your drug product contains >50% Lactose, which makes it susceptible to microbial growth. Thus, we request that you include microbial controls for the release and stability of your product. Alternatively, you may conduct a onetime test for water activity (a_w) of the finished product and provide us with the data or demonstrate by a suitable method that your formulation does not support microbial growth."

If you have taken care all these points that I have cited then I am sure you can give a response that your drug product should not require to be sterile.

I hope I was able to give some answer to your question and suggestions.

Thanks.

Masih Jaigirdar

We are moving into P3 clinical trials with a hydrogel-based product intended for topical derm application to perturbed (burned) skin. At our last Agency briefing they positioned that the product needs to be sterile. The drug product as formulated is a low bioburden, non-sterile, preserved aqueous gel packaged in a multi-dose container. There are many examples of comparable drug products currently approved for application to compromised skin that share a similar formulation and packaging characteristics yet are not sterile. Further, this product will be packaged in 120g tubes, and I am unaware of any CMO that offers sterile fill/finish for this package size. 

Any guidance from the Community on navigating this regulatory challenge would be most appreciated.