ARCHIVED — Vol. 145, No. 41 — October 8, 2011

Regulations Amending the Food and Drug Regulations (1470 ― Non-Medicinal Ingredient Formulation)

Statutory authority

Food and Drugs Act

Sponsoring department

Department of Health

REGULATORY IMPACT
ANALYSIS STATEMENT

(This statement is not part of the Regulations.)

Executive summary

Issue

Drugs contain two types of ingredients: medicinal ingredients and non-medicinal ingredients (NMIs). Medicinal ingredients are responsible for the pharmacological activities of a drug. In contrast, NMIs are substances that fulfill a variety of functions in the drug that are not intended to contribute to a drug’s pharmacological activity, but may influence such characteristics as the palatability, rate of absorption, or ease of consumption. Non-medicinal ingredients, may originate from various sources including animals, plants, minerals or synthetic materials.

Prior to being given market authorization, evidence of a product’s safety, efficacy and quality must be provided. This information is submitted in the form of a new drug submission (NDS) for Division 8 drugs and a Drug Identification Number (DIN) application for Division 1 drugs.

Currently, applications for a DIN under Division 1 must include the quantitative list of the medicinal ingredients contained in the drug and the name and quantity of each colouring ingredient that is not a medicinal ingredient. However, there is no requirement to submit a quantitative list of other NMIs contained in a drug. There is also no requirement for manufacturers to inform Health Canada of any subsequent changes to the NMIs contained in a Division 1 drug once that drug is on the market.

This is significant since NMIs play an important role in the characteristics of a final drug, and they have also been associated with disease risk as well as a wide range of adverse reactions and toxic effects.

For example, for orally administered drugs and certain products administered by injection, NMIs can modify the release patterns of the medicinal ingredient which can ultimately affect the safety and efficacy of the drug. In addition, toxicity caused by NMIs can be the result of contamination. In the absence of a product’s full formulation, Health Canada’s ability to conduct risk management activities when issues arise post-market is limited.

The use of novel NMIs is a rapidly growing trend. Since novel NMIs, by definition, have not been widely used, their risk is less well characterized than commonly used NMIs with known risks. Consequently, in Canada, inclusion of a novel NMI in a drug causes that drug to be subject to the requirements of Division 8 of the Regulations; the drug as a whole is then subject to more stringent requirements, thus ensuring that the product is appropriately tested prior to its availability on the market. In the absence of full formulation information, Health Canada cannot determine if novel NMIs are present in a Division 1 drug, which is significant given the important role they play in the characteristics of a final drug.

The potential risks associated with NMIs outlined above highlight the importance of disclosure of the formulation of a final drug.

Objectives

The purpose of the proposed regulatory amendment would be to allow Health Canada’s assessment of Division 1 drugs to consider the risks associated with their NMIs at the premarket stage. It would also allow Health Canada to identify the drugs already on the market containing specific ingredients for which an issue had been identified, thus enhancing Health Canada’s post-market risk management capacity and the protection of Canadians. Finally, it would be in line with the objectives of Health Canada’s 2004 voluntary Drug Product Formulation Request, and would increase compliance via mandatory requirements in order to improve the safety of products available to Canadians.

The proposed amendment would also strike a balanced approach that is aligned internationally and optimizes the health and safety of Canadians while not imposing an undue burden on industry.

Description

The proposed regulatory amendment would apply to prescription and non-prescription drugs intended for human and animal use that are solely regulated under Part C, Division 1, of the Food and Drug Regulations. The amendment would not affect drugs that are regulated under Division 8 of the Food and Drug Regulations (i.e. new drugs) as they are already subject to similar requirements.

The proposed changes to the Food and Drug Regulations would introduce the following requirements:

(1) The submission of a full quantitative list of all the NMIs present in a drug as part of a DIN application, within one year of registration of the proposed Regulations.

(2) That sponsors of currently marketed Division 1 drugs — except those who have already complied with the voluntary Drug Product Formulation Request and drugs for which the information submitted is still accurate — submit their full product formulations to Health Canada within one year of registration of the proposed Regulations.

(3) That subsequent changes to the formulation of a drug holding a DIN and present on the market, be submitted to Health Canada within 30 days of the change. This requirement would come into force one year following registration of the proposed Regulation.

The proposed amendment would be complementary to the regulatory amendment addressing NMI labelling recently published in the Canada Gazette, Part Ⅱ (SOR/2010-105), which requires sponsors to list the NMIs on the outer labels of drugs, with some exceptions.

Regulatory and non-regulatory options considered

Several options were identified and analyzed by Health Canada in the development of this regulatory proposal. They include the following:

Option 1: Status Quo. Continue collecting NMI formulation data on a voluntary basis through Health Canada’s voluntary Drug Product Formulation Request.

In 2004, Health Canada initiated the voluntary Drug Product Formulation Request. Since then, drug sponsors have been asked to provide their product formulations, including NMIs, as well as information on the source of these ingredients, as part of the Annual Drug Notification. As of April 2009, Health Canada had received, on a voluntary basis, NMI information for approximately 45% of marketed drugs. The majority of that information (97%) was submitted in the first year of the initiative. Because of the potential risks associated with NMIs, the limited outcome of the voluntary request for information may prevent Health Canada from providing a timely and comprehensive response in the event of a health risk. Therefore, this option was not recommended.

Option 2: Regulatory amendment. Require complete qualitative formulations, including NMI information, to be submitted in DIN applications for Division 1 drugs, and subsequent complete quantitative formulations to be submitted at the time of market notification.

Drug sponsors would be required to submit with their DIN applications a full qualitative list (i.e. names and not quantities) of the NMIs contained in their drugs. Health Canada would include this information in the assessment of the safety, efficacy and quality of the product. Subsequently, at the time of market notification, sponsors would submit the full quantitative list of the NMIs contained in their drugs. Thus, sponsors would have the opportunity to make quantitative changes to their formulations during the drug review process.

This option would allow for a more robust review of Division 1 drugs than is the current case. However, given that the effect of an NMI on a drug is dependent on its concentration, a qualitative list does not provide sufficient information for Health Canada reviewers. Furthermore, since the quantitative information would only be submitted upon market notification, this approach may duplicate review efforts and create inefficiencies in the submission process as Health Canada would be required to assess drug information twice (upon initial application and upon market notification). Therefore, this option was not recommended.

Option 3: Proposed regulatory amendment (selected option)

As described above, manufacturers would be required to submit the full quantitative list of NMIs of their drugs with their DIN applications. Health Canada would then conduct a review of the formulation in the assessment of the safety, efficacy and quality of the product. The proposed amendment would also require drug sponsors with drugs regulated under Division 1 of the Regulations and currently on the market to submit their product formulations to Health Canada within one year of the registration of the proposed amendment. This part of the amendment would play a key role in ensuring that Health Canada could track and identify products containing potentially harmful ingredients. Drug sponsors making changes to the formulation of products already on the market would be required to notify Health Canada within 30 days of the change. At present, there are thousands of drugs on the market for which Health Canada is not aware of the complete quantitative formulation.

Of all the proposed options, Option 3 would allow for the most robust evaluation of Division 1 drugs. Furthermore, Health Canada would be able to identify issues with specific ingredients during the pre-market review phase thus potentially avoiding compliance and enforcement actions, which are costly to both the regulator and industry, once the drug is on the market.

Benefits and costs

Benefits

Description	Stakeholders affected	Quantitative and/or qualitative impacts
Identification of drugs with NMIs posing a health risk.	Health Canada and the general public	Development of appropriate communications and risk management strategies. Enhancement of consumer safety.
Identification of novel NMI in drugs regulated under Division 1.	Health Canada and the general public	Reclassification of these drugs, and more comprehensive pre-market review.
Identification of NMI issues in pre-market review.	Health Canada and the general public	More detailed safety review of the drug.
Consistent availability of data on the formulation of Division 1 drugs.	Health Canada	Identification of emerging trends and better policy planning.

Costs

Description	Stakeholders affected	Quantitative and/or qualitative impacts
Development of NMI list.	Health Canada	$35K [in full time employees (FTEs)]
Review of submitted NMI using an NMI list.	Health Canada	Cost is minimal.
Hiring of additional data entry personnel.	Health Canada	$110K (in FTEs)
Updating of NMI information.	Industry	Cost is minimal.
Submission of NMI information for marketed drugs.	Industry	Cost is minimal.
Filing of changes to NMI information.	Health Canada	Costs vary with the type of filing process and supporting data required; however, procedures are in place.
Filing of changes to NMI information.	Industry	Costs vary with the manner of the change; however, procedures are in place, and filing requirements are described in existing guidance documents.
Reclassification of a drug from Division 1 to Division 8.	Health Canada	Costs vary with the amount and manner of data submitted.
Reclassification of a drug from Division 1 to Division 8.	Industry	Costs vary due to differences in supporting data needed.

Industry

Industry may benefit from increased consumer confidence in the products available on the Canadian market which may result in increased sales.

The costs to industry can be grouped as follows:

(1) Costs that would be associated with the submission of the drug NMI formulation with a new DIN application

It is recognized that for drugs following Category IV or labelling standards, there would now be a requirement for drug development to be completed by the time of DIN application, and that this may require some business practice adjustments. For example, the identity and quantity of the NMIs (such as fragrances and flavours) to be used in the drug will need to have been finalized prior to application.

Although the proposed regulatory amendment would impose new submission filing requirements on industry, it would not impose new information requirements as, under section C.02.020 of the Food and Drug Regulations, drug sponsors must maintain master production documents and written specifications for the raw materials used in their drugs, among other documentation. In addition, such information might be requested as per section C.01.013, which would allow for request of further evidence with respect to a drug, if deemed necessary. Finally, it would have a minor impact on paper burden as industry is already required to submit a paper DIN application to Health Canada and the appropriate forms are included in that package.

(2) Costs that would be associated with the submission of changes to drug NMI formulation post-market

There is no cost recovery fee associated with the review of changes to drugs regulated solely under Division 1; therefore, there would be no cost for industry associated with the submission of updated information. Also, as per C.02.020, sponsors are required to maintain records of all changes to formulation of their drugs. The cost associated with the submission of changes to formulation would be administrative in nature (i.e. the cost of collating the information and submitting it to Health Canada as well as a minor increased paper burden). This additional cost is not considered to be significant. There is a possibility that the identification of a novel NMI in the formulation could result in the drug being regulated under the more stringent requirements of Division 8, in which case the submission of additional data might be required.

(3) Costs associated with the submission of the drug NMI formulation for the 55% of sponsors who have not complied with the voluntary Drug Product Formulation Request

As outlined above, the costs associated with the submission of formulation information would be administrative in nature. Additionally, sponsors would be encouraged to use the annual notification that is currently required under section C.01.014.5 to submit their drug formulations to Health Canada. By doing so, the administrative and paper burdens associated with this part of the amendment would be minimal. In addition, there is a possibility that the identification of a novel NMI in the formulation may result in the drug being subject to the requirements of Division 8, in which case the submission of additional data might be required.

Health Canada

The proposed regulatory amendment would enhance Health Canada’s capacity to manage risks on behalf of Canadians. It would also allow the review of drugs regulated under Division 1 to include a consideration of the risks of the non-medicinal ingredients in the drug formulation. Furthermore, if a novel NMI was identified in a Division 1 drug, this could lead to the reclassification of that drug as a Division 8 drug, thereby allowing Health Canada to further examine the associated risk.

1.1 Costs

The costs to Health Canada associated with the proposed amendment would be related to the review of the formulation and to data entry. The costs can be grouped as follows:

(1) Costs that would be associated with the establishment of a list of NMIs that trigger a more extensive review of the drug

In order to ensure that the formulation review process is effective and expeditious, a list of unacceptable NMIs or NMIs requiring a more extensive review would be established. This NMI list would serve as a tool for drug reviewers in the detection of potentially hazardous NMIs. However, it would not substitute for the review as all formulations would be individually studied in the assessment of the safety, efficacy and quality of the drug. It is anticipated that costs associated with the establishment and maintenance of the NMI list by Health Canada staff would be approximately $35 000. No information technology costs are associated with the list.

(2) Costs that would be associated with the submission of the drug formulation with a new DIN application

2.1 Drug review

Health Canada drug reviewers currently review drug formulations that are submitted on a voluntary basis in DIN applications (approximately half of the DIN applications received include full formulation information). The proposed amendment would compel all sponsors to submit their drug formulations in their DIN applications; therefore, there would be an increased workload for drug reviewers as they would be required to review all the product NMI formulations. However, given that Health Canada is currently reviewing drug formulations without an NMI list (as described above), and that an NMI list will significantly facilitate the review of formulations, it is not anticipated that this part of the amendment would have a significant impact on Health Canada.

(3) Costs that would be associated with the submission of changes to drug formulation post-market

3.1 Data entry and review

Since submission of changes to product formulation is not currently mandated, Health Canada cannot anticipate the number of changes that could result from this part of the amendment, nor is it possible, due to database limitations, to extrapolate the amount based on the number of changes that occur to Division 8 product formulations. However, since Health Canada already requests the submission of information related to different types of changes to drugs regulated under Division 1 of the Regulations, the Department is already absorbing costs similar to those associated with this amendment.

There is also the potential for the identification of a novel NMI in the formulation that may result in the drug being subject to the requirements of Division 8, rather than Division 1 of the Food and Drug Regulations. In this instance, additional data might be required, which would incur costs for review. These costs would be variable. Due to the limited data on Division 1 drug NMI formulation, Health Canada cannot accurately predict the likelihood of this occurrence. However, the benefit of the disclosure of this information to the Department would still outweigh the potential cost.

(4) Costs that would be associated with the submission of the drug formulation for the 55% of sponsors who have not voluntarily addressed the Drug Product Formulation Request

4.1 Data entry

Health Canada would be required to input the formulations of all the products whose information does not appear in a Drug Product Formulation Request. Currently, 45% of sponsors have met the request. Therefore, the estimated cost of inputting the data would be limited to a one-time cost of a maximum of $110,000 (consisting of the salary dollars for the data entry personnel. No software changes are needed in response to the proposed amendment).

4.2 Review

During the data entry stage, the list of NMIs requiring a more extensive review would identify those products that necessitate further review. Based on Health Canada’s experience with the Drug Product Formulation Request, it is anticipated that the majority of products would not require further review. Therefore, it is not expected that this part of the amendment would have a significant resource impact on Health Canada.

There is also the potential for the identification of a novel NMI in the formulation that could result in the drug being subject to the requirements of Division 8, rather than Division 1 of the Food and Drug Regulations. In this instance, additional data could be required, which would incur costs of review. However, as mentioned above, Health Canada is limited in its ability to predict the likelihood of this occurrence. Nevertheless, the benefit of the disclosure of this information to the Department would still outweigh the potential cost.

Canadians

The proposed amendment would have a positive impact on Canadians since it would result in a review of drugs subject to Division 1 that considers the risks associated with their NMIs. Furthermore, it would strengthen Health Canada’s ability to track and identify drugs containing potentially harmful NMIs.

Since the expected cost of the proposed amendment to industry is minimal, it is anticipated that drug prices would not be affected.

Provincial health care systems

The improved tracking and identification of NMIs could benefit provincial health care systems in the diagnosis and treatment of patients. Additionally, this could result in fewer adverse reactions and physician visits, thus reducing costs to the provinces.

There are no anticipated costs to the provincial health care systems resulting from the proposed amendment.

Rationale

Of the three options discussed, the proposed regulatory amendment would provide the greatest benefit to Canadians relative to the cost incurred by stakeholders. First, it would allow Health Canada’s assessment of Division 1 drugs to consider the risks associated with their NMIs at the premarket stage. Second, if an issue is identified with a specific ingredient, Health Canada could identify the drugs already on the market containing this ingredient, thus enhancing Health Canada’s post-market risk management capacity and the protection of Canadians. Third, the proposed amendment would be in line with the objectives of Health Canada’s 2004 voluntary Drug Product Formulation Request, and would ensure compliance via mandatory requirements in order to improve the safety of products available to Canadians.

The proposed regulatory amendment would also be in line with the recognition of Health Canada of the significant role played by NMIs in the safety, efficacy and quality of a final product as reflected in several frameworks under the Food and Drugs Act. The amendment would align with the approach of several international organizations, with differences only due to the nature of the regulatory framework for drugs in Canada.

It is anticipated that any costs associated with this regulatory amendment would be incurred primarily by industry and Health Canada. The cost to industry is expected to be minimal and mostly administrative in nature. Given that the risks associated with NMIs could be significant, the benefits associated with the proposed amendment are considered to outweigh the known and unknown costs to Health Canada.

Consultation

This regulatory proposal was originally part of Project 743, a larger proposal first initiated in 1988 which also included amendments requiring the listing of NMIs on the outer labels of drugs. In 2006, the two initiatives were divided into Project 743, which retained the proposals for NMI labelling, and Project 1470, which was limited to NMI formulation (the current proposal).

Before the proposals were divided, extensive informal and formal consultations were undertaken with many stakeholders such as the pharmaceutical industry, consumer organizations, health care professional organizations, individual pharmacists and provincial ministries of health. These consultations included three prepublications in the Canada Gazette, Part Ⅰ, in 1989, 1994 and 1999. The majority of the work conducted by Health Canada between those years, and the vast majority of comments received through consultation, focussed on NMI labelling.

In 2004, Health Canada initiated the voluntary Drug Product Formulation Request, in which drug sponsors were asked to provide their product formulations as part of the annual drug notification. This initiative was Health Canada’s first step in acquiring NMI formulation information for Division 1 drugs independent of the NMI labelling project.

In June 2007, an early consultation letter to stakeholders was posted on the Health Canada and Consulting with Canadians Web sites. The letter outlined the approach for the regulatory proposal for NMI formulation (Project 1470) and provided a 60-day comment period.

The comments received in the 2007 consultation were in line with the comments received following pre-publication in 1989, 1994 and 1999. The comments can be summarized as follows:

(1) Stakeholder associations representing drug manufacturers commented that the product formulation is often not finalized at the time of DIN application and that the formulation should be required at the time of notification rather than in the DIN application.

Following consideration of this comment, Health Canada has determined that, in order to conduct a thorough evaluation of Division 1 drugs, it must have the full quantitative formulation at the time of review. Less information compromises the quality of the review and consequently the benefit/risk analysis of the drug.

This amendment does not preclude sponsors from modifying their product formulations following submission of the DIN application, if necessary. Since the proposed amendment will be subject to paragraph C.01.014.4(b), any changes made to the NMIs of a drug following submission of the DIN application and prior to the sale of the drug must be submitted with the market notification mandated under C.01.014.3.

(2) Stakeholders representing drug manufacturers commented that the formulation data submitted to Health Canada should be qualitative rather than quantitative. Quantitative data compromises proprietary information and creates an economic burden on industry.

Following consideration of this comment, Health Canada has determined that the Department must receive the full quantitative formulation in order to properly assess the safety, efficacy and quality of a drug.

Proprietary information submitted in any drug application is subject to the Access to Information Act and cannot be released to the public. Therefore, proprietary information will not be compromised by this regulatory proposal.

As stated above, the economic burden on industry related to this amendment is considered to be minimal.

(3) Stakeholders representing drug manufacturers commented that minor changes to formulation should be identified in the Annual Notification while more substantive changes should require a 30-day notification. This distinction would decrease the burden on industry.

This regulatory proposal would require sponsors to notify Health Canada of changes in formulation within 30 days of the change. After having considered all stakeholders’ comments, Health Canada sees a value in obtaining all information related to changes in the formulation of drug products, which could have an impact on the safety, efficacy and quality of a drug.

Implementation, enforcement and service standards

The coming into force dates of the proposed amendment would be as follows:

(1) New DIN applications

Immediately following coming into force of the proposed amendment, drug sponsors submitting any new DIN applications would be required to submit the full quantitative list of the NMIs of the drug.

(2) Division 1 drugs currently holding DINs

Division 1 drug sponsors that did not comply with the voluntary Drug Product Formulation Request would have one year following the registration of the proposed Regulations to submit to Health Canada the full quantitative list of the medicinal and non-medicinal ingredients of their products. This information would be submitted using the Drug Product Information Form, which is available on the Health Canada Web site. Drug sponsors who have already complied with the voluntary Drug Product Formulation Request would not be required to resubmit their formulation information except in cases of updates to the previously submitted information.

Similarly, Division 1 drug sponsors would have one year following the registration of the proposed Regulations prior to being subject to the 30-day notification requirement for changes to formulation.

This proposed amendment would neither alter existing compliance and enforcement mechanisms, nor affect current drug submission service standards.

Performance measurement and evaluation

The proposed amendment would be evaluated over time for the success of its implementation with respect to (1) the submission of NMI information at the time of the DIN application, and potential changes to such data; and (2) its effectiveness in enabling the identification of products implicated in situations where a health risk has been identified for a particular NMI, and the consequent ability to incorporate that information into risk-management actions.

Contact

Refer to Project No. 1470
Bureau of Policy, Science and International Programs
Therapeutic Products Directorate
Health Canada
Holland Cross, Tower B, 2nd Floor
1600 Scott Street
Address Locator: 3102C5
Ottawa, Ontario
K1A 0K9
Telephone: 613-948-4623
Fax: 613-941-6458
Email: regaff-affreg@hc-sc.gc.ca.

PROPOSED REGULATORY TEXT

Notice is hereby given that the Governor in Council, pursuant to subsection 30(1) (see footnote a) of the Food and Drugs Act (see footnote b), proposes to make the annexed Regulations Amending the Food and Drug Regulations (1470 — Non-Medicinal Ingredient Formulation).

Interested persons may make representations concerning the proposed Regulations within 75 days after the date of publication of this notice. All such representations must cite the Canada Gazette, Part Ⅰ, and the date of publication of this notice, and be addressed to Policy Division, Bureau of Policy, Science and International Programs, Therapeutic Products Directorate, Department of Health, 1600 Scott Street, Holland Cross, Tower B, 2nd Floor, Address Locator: 3102C5, Ottawa, Ontario K1A 0K9 (fax: 613-941-6458; email: regaff-affreg@hc-sc.gc.ca).

Ottawa, September 29, 2011

JURICA ČAPKUN
Assistant Clerk of the Privy Council

REGULATIONS AMENDING THE FOOD AND DRUG REGULATIONS (1470 — NON-MEDICINAL INGREDIENT FORMULATION)

AMENDMENTS

1. Paragraph C.01.014.1(2)(h) of the Food and Drug Regulations (see footnote 1) is replaced by the following:

• (h) a quantitative list of the drug’s non-medicinal ingredients;
  

2. The Regulations are amended by adding the following after section C.01.014.7:

C.01.014.8 (1) A manufacturer is prohibited from selling a drug in respect of which, before the day on which this subsection comes into force, a drug identification number has been assigned or an application for a drug identification number has been made, unless a quantitative list of the drug’s non-medicinal ingredients has been provided to the Director.

(2) A list that has been provided to the Director before the day on which subsection (1) comes into force does not satisfy the condition in that subsection if the list is not accurate on that day.

(3) For greater certainty, paragraph C.01.014.4(b) applies in respect of a change in the subject matter of a list that has been provided to the Director.

COMING INTO FORCE

3. These Regulations come into force on the day that is one year after the day on which they are registered.

[41-1-o]

• Footnote a
  S.C. 2005, c. 42, s. 2
• Footnote b
  R.S., c. F-27
• Footnote 1
  C.R.C., c. 870