Health Canada GMP Program

Certificate Program in Regulatory Leadership Stephen McCaul, A/Manager, GMP, Central

February 7, 2018

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Overview

• Who we are and what we do

– Domestic Inspection Program

– Foreign Inspections and International Collaboration

– Foreign Building Paper Assessments

– Risk Assessments • Challenges, Opportunities, Risks & Pressures

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Our work at Health Canada • Health Product Inspection and Licensing Division (HPIL):

– Manage and deliver a national compliance and enforcement program for drug products collaborating with and across all regions.;

• Drug Establishment Licensing and Invoicing; • Good Manufacturing Practices (GMP) program; and • International engagement and MRA program.

• In GMP, we regulate the pharmaceutical industry by conducting

– Domestic on-site inspections – Foreign on-site inspections – Paper assessments of inspections done by other regulators – Risk files of foreign suspected non-compliant inspections

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What are Good Manufacturing Practices (GMP)?

• Set of principles related to quality assurance that helps in ensuring that drugs are consistently produced, controlling the quality standards appropriate to the intended use of the drug, and meeting the specifications required by the marketing authorization.

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Canadian Legal Framework

Legislation and Regulations • Food and Drugs Act (FDA) • Food and Drug Regulations (FDR)

Import and sale

1. There must be a person in Canada responsible for the sale of a drug

2. The drug(s) must have been fabricated, packaged, labelled, tested and stored in accordance with Division 2 Good Manufacturing Practices of the FDR

• Premises, Personnel, Manufacturing Control, Quality Control, Finished Product Testing, Records, Samples, Stability

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FDR In Canada these requirements are defined in Part C, Division 2 of our Food and Drug Regulations. Prohibition on sale C.02.003. No distributor referred to in paragraph C.01A.003(b) and no importer shall sell a drug unless it has been fabricated, packaged/labelled, tested and stored in accordance with the requirements of this Division. Prohibition - C.01A.004 • (1) Subject to subsection (2), no person shall, except in accordance with an establishment

licence, • (a) fabricate, package/label or import a drug; • (b) perform the tests, including examinations, required under Division 2; • (c) distribute a drug as set out in section C.01A.003 that is not an active

pharmaceutical ingredient; or • (d) wholesale a drug that is not an active pharmaceutical ingredient

Application - C.01A.005 • (l) evidence that the applicant’s buildings, equipment and proposed practices and procedures

meet the applicable requirements of Divisions 2 to 4;

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• Compliance and Enforcement (C&E) Policy (POL-0001) is used to determine the appropriate C&E action based on the observations and corrective actions.

• Examples of POL-0001 C&E actions: – Suspension of Establishment license (Immediate or Proposal to Suspend) – Terms and conditions (ex – Additional testing to allow importation of

medically necessary drugs) – Regulatory stop sale – Product Recall – Public warning/advisory letter – Warning Letter

* The medical necessity of a product is a factor that is considered when determining the appropriate C&E action. This is based on the risk/benefit analysis conducted as part of the medical necessity determination assessment

Compliance Policy

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MEDICALLY NECESSARY

Health Canada defines a medically necessary drug as, “a market-authorized drug in Canada which is used to prevent, treat or diagnose a serious or life-threatening disease or medical condition, for which there is no available alternative.”

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• Mutual Recognition Agreements (MRA) • Pharmaceutical Inspection Co-Operation Scheme (PIC/S) • International Conference on Harmonization (ICH) • Regulatory Cooperation Council with the United States Food and Drug

Administration (RCC HC - US FDA) • Regulatory Cooperation Initiative with Australia’s Therapeutic Goods

Administration (RCI HC-TGA)

Health Canada collaborates with regulatory partners to enhance partnerships, work sharing, foster

harmonisation, and share expertise

International Collaboration

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International legally binding treaty between 2 parties

• Recognize equivalency of drug GMP compliance programs between regulatory authorities

• Exchange of Certificates of Compliance (CoCs) between 2 countries • Recognized within the framework of the World Trade Organization • Canada currently has MRAs with

• EU • Switzerland • EEA-EFTA • Australia

Mutual Recognition Agreement

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What is PIC/S?

A voluntary agreement/scheme with the interest of public health to:

• Establish international cooperation in GMP/GDP inspections to maintain mutual confidence and quality of inspections

• Share information and experience • Coordinate mutual training of inspectors

48 Participating Authorities including… • European Commission, Switzerland, Australia, Singapore, Malaysia, South

Africa, Argentina, Canada, Israel, New Zealand, USA, Taiwan, Indonesia, Croatia, Hong Kong

• 4 partners of PIC/S (EDQM, EMA, UNICEF, WHO)

Link: http://www.picscheme.org/members.php

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Why we collaborate • Currently, we only have the capacity to conduct 40-45 foreign on-site

inspections in a year. We can’t do it alone. • So, we collaborate with other trusted regulators (FDA, EU, TGA, etc) to

inspect the foreign sites and share the GMP evidence. – Conduct joint inspections – Exchange GMP evidence – Harmonize regulatory guidance

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DOMESTIC INSPECTIONS

Frequency 1-4 years, depending on risk/ activity Fabricators: 2-3 years, mostly 3 years Importers: 4 years Duration 1-10 days, depending on activity Fabricators: 5-10 days, based on risk Importers: 3-4 days

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What we do – Domestic Inspections

Activities Fabricators – sterile, or non-sterile Packagers/labellers Tester Importer Distributor Wholesaler

Domestic Drug Industry

FabricatorsPackager/ LabellersTestersImportersDistributorsWholesalers

426 (26%)

159 (10%)

234 (14%)

202 (13%)

406 (25%)

188 (12%)

As of May 2017

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Domestic Compliance Ratings

CompliantNon-compliantNo RatingCompliant 95%

NR <1% NC 4%

*NC varies year-year

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2016-17

FOREIGN ON-SITE ASSESSMENTS

To add or maintain a foreign building on an importer’s licence, an importer must have evidence to demonstrate GMP compliance of the foreign site.

The evidence to support the GMP compliance of a foreign building can be: Health Canada on-site inspection (aka on-site assessment) Inspection by a qualified regulatory authority (paper assessment)

Limited duration 4-10 days (typically 5 days) Risk based scheduling:

Mainly inherently higher risk and more complex fabricators – FDF (finished dosage form)/ API (active pharmaceutical ingredient), sterile manufacturing Many sites have had compliance issues, e.g., Data integrity

Requires highly trained inspectors.

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What we do – Foreign Inspections

India 42%

USA 22%

China 17%

Mexico 7%

Argentina 3%

Chile 3%

Columbia 3%

Israel 3%

Health Canada FY 17/18 on-site inspections by country

Landscape China: 60 FDF/Sterile API 241 Non-sterile API India: 205 FDF/Sterile API 300 Non-sterile API United States: 766 FDF/Sterile API 359 Non-sterile API

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Joint/ consecutive foreign inspections with other regulators

2017-18

HC alone (30)HC/FDA (4)HC/TGA (4)HC/MHRA (1)HC/TGA/MHRA

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Compliance of Foreign On-Site Assessments

Compliant 23

85%

Non-compliant

4 15%

Foreign Compliance (FY 2016-2017)

Compliant 23

88%

Non-compliant

3 12%

Foreign Compliance (FY 2017-2018)

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PAPER ASSESSMENTS

Health Canada conducts paper assessments of GMP evidence submitted in support of an application or proactively requested by Health Canada. The type of GMP evidence can be: • Certificate of Conformance (for sites located in MRA countries) (460) • Qualified Regulatory Authority inspection report (for sites located in non-

MRA countries, etc), e.g., PIC/S Inspectors assess the inspection reports and determine whether the foreign building is compliant with Division 2 of the Food and Drug Regulations, similar to a paper assessment.

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What we do – Paper Assessments and Risk Files

Health Canada is monitoring foreign compliance information:

– US FDA Warning Letters – US FDA Import Alerts – US FDA 483 – EDQM CEP Suspensions (Certificate of Suitability) – Media Articles – Information Provided by Canadian companies – Information from other Regulatory Authorities

Monitoring Risk

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• Once a risk trigger is identified, Health Canada determines the impact on the Canadian market.

• Health Canada contacts the Canadian importers and requests GMP related

information. This information includes but is not limited to: – Products and quantity, Medically Necessity, Foreign Buildings corrective actions,

Importers risk assessment

• If an importer suggests a product to be medically necessary, Health Canada pre-market directorates assess the information provided to determine whether the product in question meets Health Canada’s definition of medically necessary.

Management of Risk Triggers

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Challenges and Opportunities Global Drug Supply Chain Canada imports:

more drugs than it produces domestically increasing number of drugs produced abroad in emerging markets increasing number of innovative drugs and new technologies

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To date, there are approximately 4000 foreign buildings that fabricate, package, label or test drugs for the Canadian market.

Through Domestic inspections of Importers, we find: •Inadequate quality agreements and information sharing between manufacturer and Importer •Some Importers do not fully understand the manufacturing supply chain for drugs they import •Some Importers have inadequate amount of oversight of foreign building from a quality/ regulatory perspective

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Risks and Pressures • 21% of foreign buildings manufacturing drugs for the

Canadian market are located in countries outside the jurisdiction of our trusted regulatory partners.

• Complex inspection issues have emerged from foreign inspections (e.g. data integrity), causing us to re-think how we inspect

• There is a higher risk of importing counterfeit and contaminated drugs.

• We need to be more agile and present globally while maintaining adequate oversight on domestic establishments

• We have limited resources to inspect overseas.

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New challenges - Data Integrity • “the extent to which all data are complete, consistent

and accurate throughout the data lifecycle” (MHRA) • Data must be Attributable, Legible, Contemporaneously

recorded, Original or true copy, Accurate • Subject of several FDA warning letters, compliance

action, import bans, serious fines • Examples:

– Manipulation of lab data (trial injections), Deleted or fabricating data, Backdating, Re-running samples/ testing into compliance, Non-secure computer access

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Regulatory response to DI • Inspectors had to quickly to learn, adapt and react • First treated as a risk file, serious compliance action taken,

then an on-site inspection • Required a swift response by regulators to

– Understand and interpret the risk – Develop inspector training – Write regulatory guidance

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KEY MESSAGES Health Canada maintains robust regulatory oversite of the domestic and foreign drug industry. The level of GMP compliance in foreign countries that are not part of important international regulatory partnership schemes is lower. Effective international collaboration between regulators is essential to help ensure GMP compliance of foreign suppliers, share knowledge and experience and harmonize regulatory requirements. Regulators must stay sharp and agile in order to address new challenges.

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THANK YOU

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