Regulatory Open Forum

Hi Every one,

I have 3 actives in the drug product and we are trying to reclassify one of the actives as excipient. Could any one suggest the best possible strategy to put this change to health authorities in Europe. The ingredient i am trying to downgrade from being an API to excipient was included in the formulation primarily for its action to potentiate one of the active ingredients to act against gram negative bacteria. There is no other product in the market with this ingredient as API.  There is no support in terms of CEP or ASMF. The ingredient is also manufactured by chemical supplier's who do not fall under the scope of GMP., which is making it harder to maintain the status as API. My arguement is to downgrade it to excipient citing the primary reason for inclusion is for its potentiation activity to one of the ingredients but it does not produce any therapeutic action on its own.

Please feel free to add your thoughts and challenge the approoach so that i can gather enough evidence for the strategy.



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Regulatory Consultant

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For what it is worth this situation has repeatedly emerged in the US OTC industry regulated mostly by the monograph system.  Somewhat cynically in the 1980's I named this "The Trojan Horse" approach.  The name stuck within certain circles.  For over-the-counter drugs the Trojan Horse process can take several forms.  For example, an API like menthol might be reduced to below the concentration range in a topical product and be listed as an inactive. That level might be "active", or contribute other organoleptic attributes to the formula.  The inactive needs to be seen as a pharmaceutical necessity or have a reason for being.  Similar challenges are seen with topical penetration enhancers, controlled release formulations, etc. that alter the PK/PD of the product.  There are lists of accepted GRAS excipients that may apply to your geographies.  Your point is well taken.  

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Donald Riker, PhD
On Point Advisors, LLC
Chattanooga TN
United States
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Original Message:
Sent: 04-09-2014 11:03
From: Vikram Gummadi
Subject: Reclassification of Ingredient from API to excipient

Hi Every one,

I have 3 actives in the drug product and we are trying to reclassify one of the actives as excipient. Could any one suggest the best possible strategy to put this change to health authorities in Europe. The ingredient i am trying to downgrade from being an API to excipient was included in the formulation primarily for its action to potentiate one of the active ingredients to act against gram negative bacteria. There is no other product in the market with this ingredient as API.  There is no support in terms of CEP or ASMF. The ingredient is also manufactured by chemical supplier's who do not fall under the scope of GMP., which is making it harder to maintain the status as API. My arguement is to downgrade it to excipient citing the primary reason for inclusion is for its potentiation activity to one of the ingredients but it does not produce any therapeutic action on its own.

Please feel free to add your thoughts and challenge the approoach so that i can gather enough evidence for the strategy.



-------------------------------------------

Regulatory Consultant

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You'll most likely need in vitro and/or clinical data with and without the potentiator to show that this action is irrelevant. Otherwise, I don't see how you'll be able to downgrade it to an excipient. Presumably the action on the gran negative bacteria in your product is important so this approach would not workl.

-------------------------------------------
Mary Jarosz RAC
Vice President of QA/RA
WomanCare Global
Cardiff By The Sea CA
United States
-------------------------------------------






Original Message:
Sent: 04-09-2014 11:03
From: Vikram Gummadi
Subject: Reclassification of Ingredient from API to excipient

Hi Every one,

I have 3 actives in the drug product and we are trying to reclassify one of the actives as excipient. Could any one suggest the best possible strategy to put this change to health authorities in Europe. The ingredient i am trying to downgrade from being an API to excipient was included in the formulation primarily for its action to potentiate one of the active ingredients to act against gram negative bacteria. There is no other product in the market with this ingredient as API.  There is no support in terms of CEP or ASMF. The ingredient is also manufactured by chemical supplier's who do not fall under the scope of GMP., which is making it harder to maintain the status as API. My arguement is to downgrade it to excipient citing the primary reason for inclusion is for its potentiation activity to one of the ingredients but it does not produce any therapeutic action on its own.

Please feel free to add your thoughts and challenge the approoach so that i can gather enough evidence for the strategy.



-------------------------------------------

Regulatory Consultant

-------------------------------------------

Consider the following:You can "rename it" but if it is novel, then it is very similar to an API.

Dar

Examples of novel excipients developed recently are as follows:
Characterization of novel excipients
Generally novel excipients are characterized for three important properties domains:

Functionality
This involves pharmaceutical assessment and investigation of drug delivery properties. For this study, different formulations containing novel excipient along with already existing approved excipients are prepared and are assessed for different tests such as dissolution testing. In vitro dissolution testing provides prediction of in vivo bioavailability. 

Physicochemical properties
It involves assessment of physicochemical properties of excipients, impurities profiling, and stability assessment. This characterization involves spectroscopic, chromatographic, thermal methods of analysis. During this analysis, viscosity, rheology, melting point, specific gravity, refractive index, acid and ester values, loss on heating and drying, pH value, heavy metals, residual solvents and monomers were determined.

Safety / toxicology
During this study, ICH M4S (R2) guideline is followed for generation of safety data. Chronic and sub-chronic toxicity, genotoxicity (including mutagenicity), reproductive toxicity, carcinogenicity, primary irritation and skin sensitization testing, bioavailability, pharmacokinetics (ADME) and characterization of impurities and their toxicity are done in this study domain. 

Regulatory provisions
Question arises in minds whether  excipients are actually inert? Historically, Sulfanilamide tragedy 1937 happened due to lack of knowledge about excipients' use. This gave us regulatory reforms leading to development of regulatory guidelines regarding excipients. 

Currently, there is no special provision for approval of new excipients. Excipients are approved along with the dosage forms. Excipient is regarded as "approved" when the new drug formulation containing  novel excipient received regulatory approval. Existing guidelines do not provide guidance on potentially useful excipients from food / beverage industries or for excipient with a new application such as changing dose route.  But still pharmaceutical excipient companies are investing in evaluation of new materials and application of new uses for existing excipients.

In 3.2.P.4.6 Section of International Conference on Harmonization (ICH) M4 Q (R1) step 4 guideline following is mentioned: 

For excipient(s) used for the first time in a drug product or by a new route of administration, full details of manufacture, characterization, and controls, with cross references to supporting safety data (nonclinical and/or clinical) should be provided according to the drug substance format. 

Similarly European Medicines Agency has given following guidelines in Section 4.5 with following details :

For novel excipients, a dossier should be established containing the same data as required for new active substances:

• A strict definition of the excipient, its function and its conditions of use. If the excipient is complex or is made of a mixture of compounds, the composition should be specified in qualitative and quantitative terms.
• For novel excipients and for excipients presented as a mixture of compounds the following should be taken into consideration:
• Any bibliographical data on the chemistry and on the toxicology and the field in which the product is already used.
• The community provisions concerning additives in foodstuffs: any criteria which are based on the toxicological data, with cross-references to these data.
• The quality specifications which have been laid down in the directives are satisfactory as long as the routine control tests used are validated.
• The international specifications (FAO/ WHO/ JECFA), and other publications such as the Food Chemical Codex.
• For medicinal products for cutaneous use, data on the starting material in cosmetic products.
• Data concerning the toxicology of the novel excipient should be presented according to the dosage form and the route of administration of the medicinal product (if applicable).
• Documentation on chemistry of excipients is required for all new excipients, taking as its basis the CPMP Guideline on the Chemistry of New Active Substances
• The origin of the excipient, including the name and address of manufacturer.
• A general outline of the synthesis (manufacture and purification).
• Structure.
• Physical, chemical properties, identification and purity tests.
• Validated methods of analysis with a presentation of batch results.
• Miscellaneous information (microbiological tests, etc).
• Contamination, presence of foreign substances, residual solvents etc.
• In the case of an excipient obtained from a mixture of several components, the quality of each component and the physiochemical tests for the mixture should be described.
• Stability data should be provided as required for the active substances in the ICH Q1A
• The routine test procedures and limits should be established on the basis of the documentation given in the dossier.

International Pharmaceutical Excipients Council (IPEC) is working for harmonization and setting up guidelines for novel excipients. IPEC has set up excipient master file guide for novel excipients as Type IV Drug master file (DMF). This guide has been divided into administrative information and technical document portion. Technical document is similar to ICH Common technical document (CTD) portion with 15 points. 

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Darlene Rosario
Principal Consultant RA, Quality and Compliance
Velocity Consulting
Ventura CA
United States
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Original Message:
Sent: 04-10-2014 09:46
From: Mary Jarosz
Subject: Reclassification of Ingredient from API to excipient

You'll most likely need in vitro and/or clinical data with and without the potentiator to show that this action is irrelevant. Otherwise, I don't see how you'll be able to downgrade it to an excipient. Presumably the action on the gran negative bacteria in your product is important so this approach would not workl.

-------------------------------------------
Mary Jarosz RAC
Vice President of QA/RA
WomanCare Global
Cardiff By The Sea CA
United States
-------------------------------------------






Original Message:
Sent: 04-09-2014 11:03
From: Vikram Gummadi
Subject: Reclassification of Ingredient from API to excipient

Hi Every one,

I have 3 actives in the drug product and we are trying to reclassify one of the actives as excipient. Could any one suggest the best possible strategy to put this change to health authorities in Europe. The ingredient i am trying to downgrade from being an API to excipient was included in the formulation primarily for its action to potentiate one of the active ingredients to act against gram negative bacteria. There is no other product in the market with this ingredient as API.  There is no support in terms of CEP or ASMF. The ingredient is also manufactured by chemical supplier's who do not fall under the scope of GMP., which is making it harder to maintain the status as API. My arguement is to downgrade it to excipient citing the primary reason for inclusion is for its potentiation activity to one of the ingredients but it does not produce any therapeutic action on its own.

Please feel free to add your thoughts and challenge the approoach so that i can gather enough evidence for the strategy.



-------------------------------------------

Regulatory Consultant

-------------------------------------------

Darlene,

You did a nice job of defining the issues if the material is a novel excipient.  However, I am not sure that is the problem here.  We would need Vikram to specify if the material is already used as an excipient in other drug applications in Europe or not.  It kind of sounds like that is the case from his comment below.  If so, then the novel excipient issues would not apply. 

It appears that what Vikram really wants to do is re-classify an atypical active (an excipient being used as an active) as an excipient in this application so that he doesn't have to deal with the Q7 GMP expectations for APIs in Europe under the Falsified Medicines Directive.  The key question to me is to understand why this material was classified as an active to start with in the original application since there already are other actives in the formulation.  What is the specific function of this material and why wasn't it considered to be an excipient in the first place?  This would be critical in determining what can be done and how it needs to be classified.

All that said, we have been having many discussions lately at IPEC-Americas about the issue of atypical actives and the fact that most of these materials which are mainly being used as an excipient will never be produced using Q7 GMPs regardless of what regulators might want because there are no economics that would support this due to the very small use of these materials as an API. 

I recently testified on behalf of IPEC-Americas at the recent FDA OTC Monograph Hearing and talked about the Atypical Actives issue and the fact that FDA needs to find a way to allow these excipients to be used as atypical actives without expecting that Q7 GMPs will be used.  IPEC-Americas is developing a proposal for how this could be done and will be submitting comments to FDA concerning this before the May 12th deadline for comments.  IPEC-Americas will be requesting a meeting with FDA to discuss this issue in our comments.  Hopefully we will make some progress with FDA on how this could be done.  Once we come up with some agreements with FDA on how to handle atypical actives, we hope to discuss this issue with EU regulators as well.

I don't think this will help Vikram much with his current situation since this will be a longer term resolution.  However, Vikram will have to have a similar discussion with EU regulators about what is possible and what is not for his drug product.  I don't think he will simply be able to re-classify the API as an excipient without a significant scientific explanation about what the functionality is and why there is no real API action.

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David Schoneker
Dir, Global Regulatory Affairs
Colorcon
West Point PA
United States
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Original Message:
Sent: 04-11-2014 11:03
From: Darlene Rosario
Subject: Reclassification of Ingredient from API to excipient

Consider the following:You can "rename it" but if it is novel, then it is very similar to an API.

Dar

Examples of novel excipients developed recently are as follows:
Characterization of novel excipients
Generally novel excipients are characterized for three important properties domains:

Functionality
This involves pharmaceutical assessment and investigation of drug delivery properties. For this study, different formulations containing novel excipient along with already existing approved excipients are prepared and are assessed for different tests such as dissolution testing. In vitro dissolution testing provides prediction of in vivo bioavailability. 

Physicochemical properties
It involves assessment of physicochemical properties of excipients, impurities profiling, and stability assessment. This characterization involves spectroscopic, chromatographic, thermal methods of analysis. During this analysis, viscosity, rheology, melting point, specific gravity, refractive index, acid and ester values, loss on heating and drying, pH value, heavy metals, residual solvents and monomers were determined.

Safety / toxicology
During this study, ICH M4S (R2) guideline is followed for generation of safety data. Chronic and sub-chronic toxicity, genotoxicity (including mutagenicity), reproductive toxicity, carcinogenicity, primary irritation and skin sensitization testing, bioavailability, pharmacokinetics (ADME) and characterization of impurities and their toxicity are done in this study domain. 

Regulatory provisions
Question arises in minds whether  excipients are actually inert? Historically, Sulfanilamide tragedy 1937 happened due to lack of knowledge about excipients' use. This gave us regulatory reforms leading to development of regulatory guidelines regarding excipients. 

Currently, there is no special provision for approval of new excipients. Excipients are approved along with the dosage forms. Excipient is regarded as "approved" when the new drug formulation containing  novel excipient received regulatory approval. Existing guidelines do not provide guidance on potentially useful excipients from food / beverage industries or for excipient with a new application such as changing dose route.  But still pharmaceutical excipient companies are investing in evaluation of new materials and application of new uses for existing excipients.

In 3.2.P.4.6 Section of International Conference on Harmonization (ICH) M4 Q (R1) step 4 guideline following is mentioned: 

For excipient(s) used for the first time in a drug product or by a new route of administration, full details of manufacture, characterization, and controls, with cross references to supporting safety data (nonclinical and/or clinical) should be provided according to the drug substance format. 

Similarly European Medicines Agency has given following guidelines in Section 4.5 with following details :

For novel excipients, a dossier should be established containing the same data as required for new active substances:

• A strict definition of the excipient, its function and its conditions of use. If the excipient is complex or is made of a mixture of compounds, the composition should be specified in qualitative and quantitative terms.
• For novel excipients and for excipients presented as a mixture of compounds the following should be taken into consideration:
• Any bibliographical data on the chemistry and on the toxicology and the field in which the product is already used.
• The community provisions concerning additives in foodstuffs: any criteria which are based on the toxicological data, with cross-references to these data.
• The quality specifications which have been laid down in the directives are satisfactory as long as the routine control tests used are validated.
• The international specifications (FAO/ WHO/ JECFA), and other publications such as the Food Chemical Codex.
• For medicinal products for cutaneous use, data on the starting material in cosmetic products.
• Data concerning the toxicology of the novel excipient should be presented according to the dosage form and the route of administration of the medicinal product (if applicable).
• Documentation on chemistry of excipients is required for all new excipients, taking as its basis the CPMP Guideline on the Chemistry of New Active Substances
• The origin of the excipient, including the name and address of manufacturer.
• A general outline of the synthesis (manufacture and purification).
• Structure.
• Physical, chemical properties, identification and purity tests.
• Validated methods of analysis with a presentation of batch results.
• Miscellaneous information (microbiological tests, etc).
• Contamination, presence of foreign substances, residual solvents etc.
• In the case of an excipient obtained from a mixture of several components, the quality of each component and the physiochemical tests for the mixture should be described.
• Stability data should be provided as required for the active substances in the ICH Q1A
• The routine test procedures and limits should be established on the basis of the documentation given in the dossier.

International Pharmaceutical Excipients Council (IPEC) is working for harmonization and setting up guidelines for novel excipients. IPEC has set up excipient master file guide for novel excipients as Type IV Drug master file (DMF). This guide has been divided into administrative information and technical document portion. Technical document is similar to ICH Common technical document (CTD) portion with 15 points. 

-------------------------------------------
Darlene Rosario
Principal Consultant RA, Quality and Compliance
Velocity Consulting
Ventura CA
United States
-------------------------------------------






Original Message:
Sent: 04-10-2014 09:46
From: Mary Jarosz
Subject: Reclassification of Ingredient from API to excipient

You'll most likely need in vitro and/or clinical data with and without the potentiator to show that this action is irrelevant. Otherwise, I don't see how you'll be able to downgrade it to an excipient. Presumably the action on the gran negative bacteria in your product is important so this approach would not workl.

-------------------------------------------
Mary Jarosz RAC
Vice President of QA/RA
WomanCare Global
Cardiff By The Sea CA
United States
-------------------------------------------






Original Message:
Sent: 04-09-2014 11:03
From: Vikram Gummadi
Subject: Reclassification of Ingredient from API to excipient

Hi Every one,

I have 3 actives in the drug product and we are trying to reclassify one of the actives as excipient. Could any one suggest the best possible strategy to put this change to health authorities in Europe. The ingredient i am trying to downgrade from being an API to excipient was included in the formulation primarily for its action to potentiate one of the active ingredients to act against gram negative bacteria. There is no other product in the market with this ingredient as API.  There is no support in terms of CEP or ASMF. The ingredient is also manufactured by chemical supplier's who do not fall under the scope of GMP., which is making it harder to maintain the status as API. My arguement is to downgrade it to excipient citing the primary reason for inclusion is for its potentiation activity to one of the ingredients but it does not produce any therapeutic action on its own.

Please feel free to add your thoughts and challenge the approoach so that i can gather enough evidence for the strategy.



-------------------------------------------

Regulatory Consultant

-------------------------------------------