Recent changes in Health Canada’s GMP inspection function include a reorganization and renaming from “the Inspectorate” to “the Regulatory Operations and Enforcement Branch” (ROEB) with inspectors dedicated and directed under a centralized program and performing only drug GMP inspections.

New regulatory authorities include the ability to stop and enter a conveyance such as a semi-trailer, to compel a company to respond to its information requests and to declare during a remote inspection that documents not supplied within a specified time frame will be considered not available, thus, subject to being cited as an inspection deficiency.

[Related: Download a special report covering the state of remote inspections FY2020, including a look at how virtual reality could be integrated into a remote inspection.]

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At the International GMP Conference held virtually in March 2021, co-sponsored by the University of Georgia at Athens and FDA, Health Canada ROEB inspector Kent Downing presented an overview of recent inspection activities by his agency, providing insights into:

  • The recently-formed ROEB
  • Granting and function of drug establishment licenses in Canada
  • The agency’s new authorities
  • Processes being used by his agency to conduct remote and hybrid inspections and video conferencing tools that mandate the use of protected B video conferencing options
  • Compelling case studies from recent drug GMP inspections illustrating agency concerns and findings and providing lessons learned

Background on Health Canada Inspections

Downing pointed out that Canada’s population is approximately 38 million, or less than 10% of the U.S. population. Two-thirds of Canadians live within a one-hour drive of the US border. “I am based in Vancouver, which is on the West Coast, three hours north of Seattle by car,” he said. “I grew up outside Niagara Falls, which is right on the U.S. border.”

On average, he explained, “most Canadians” are close to and aware of what happens across the border. “And when the Canadian dollar is high, I am sure everyone in the Northern states is aware of Canadians.”

Both countries rely heavily on foreign suppliers. The pharmaceutical trade numbers and statistics from 2019 show that imports were double the exports for both the United States and Canada.

Health Canada’s drug GMP inspection unit now known as the ROEB is under Health Product Inspection and Licensing. It now has dedicated GMP inspectors and is no longer under direct regional management. Inspectors are dedicated and directed under a centralized program. So instead of being generalist inspectors that perform cross-product classifications, they are now dedicated solely to drug GMP inspections.

The agency has approximately 55 inspectors dedicated to drug GMP inspections who perform between 300 and 400 inspections a year and 600 foreign paper assessments. It is a member of PIC/S, like the U.S. FDA. It has mutual recognition agreements with Europe and Australia in which the participating agencies accept each other’s drug GMP inspections, similar to the U.S. FDA arrangement with Europe.

Drug Establishment Licenses and Domestic Inspections

In Canada, anyone who touches a drug product or an API needs a drug establishment license (DEL). Figure 1 shows the requirements for and distribution of DEL holders. Note that the agency’s inventory of foreign establishments is listed under import licenses.

Figure 1 Health Canada Drug Establishment Licenses
FIGURE 1 | Health Canada Drug Establishment Licenses

As of March 2020—a year ago—Health Canada postponed domestic onsite GMP inspections and implemented other ways of conducting inspections, such as using remote tools.

The agency contacts applicants in advance and before it conducts a review of an establishment. Onsite inspections are conducted on a case-by-case basis based on an identified health risk. It also conducts inspections when an establishment is getting ready to manufacture a new medically necessary drug or a drug that is considered important for COVID-19.

“We continue to monitor the situation as it evolves and remain flexible and adapt our approach for the health and safety of Canadians,” Downing explained. “Depending on the regional public health orders at the time and the capability of a company to host remote inspections, we have been doing remote and hybrid inspections.”

Health Canada Granted New Authorities

New regulatory authorities were given to inspectors to conduct inspections using telecommunication tools in 2019. This was added as part of the Canadian government’s regulatory modernization initiative pre-pandemic. It added inspector powers that include stopping and entering a conveyance such as a semi-trailer.

In addition, the new regulations state that inspectors are considered to have entered a place when accessing it remotely by a means of telecommunication. “That means that we can compel a company to respond to our information requests and use the tools of telecommunication,” he pointed out.

Health Canada Remote Inspections

In the past year, Health Canada has been doing remote and hybrid domestic inspections. A remote GMP evaluation is the process of conducting an inspection by means of technology for communicating, sharing, and reviewing documentation without the requirement for an inspector to be onsite.

Hybrid GMP inspections are accomplished by means of technology for communicating, sharing, and reviewing documentation with the requirement for an inspection to be onsite for a period of time to evaluate all the physical aspects that are difficult to assess remotely.

In the recent past, remote inspections were targeted for sites with low-risk activities and compliant histories. “It was originally envisioned as a carrot for compliant companies to have a remote inspection with a limited inspection burden that would be good for our regular inspection cycle,” Downing noted.

The agency has approximately 55 inspectors dedicated to drug GMP inspections

“We have been performing hybrid inspections for sterile product sites or for urgent new COVID essential priority medicines or for cause. Those inspections have only one inspector onsite for a brief amount of time. And the rest is done as a remote inspection.”

There was a period in late summer 2020 when COVID case counts were down in Canada, and there was a drive to do everything as a hybrid inspection. However, in the fall and the winter the COVID case counts went up and the agency resumed conducting mostly remote GMP inspections.

Health Canada is piloting a video conferencing tool called VidCruiter. It is a protected B video conferencing option that protects confidential business information.

Some sites have wanted to use an alternative video conferencing tool. The agency recommendation is to use the protected platform that has been evaluated by the inspectorate. “If a company assumes the risk of sending us protected B information through another platform, we may allow it on a case-by-case basis,” Downing said.

How Firms Can Prepare for Remote Inspections

Downing explained how Health Canada’s inspection process is conducted. It begins with a formal notification email to the sites in which it informs the party that the establishment inspection will be conducted via video conference. A test link is supplied to make sure that there are no connectivity issues.

It also gives the opportunity for that site to be excluded, for instance, if they do not have the capability, the connectivity, or the computer software to do this. The agency also requests information for the company to assist in inspection planning as part of the preinspection request.

While the inspection is announced in advance, the timing can be negotiated within limits. “We make the announcement, then there is negotiation regarding if they are available and if they can connect using their computer systems,” Downing explained.

Health Canada is piloting a video conferencing tool called VidCruiter

“We also describe what we expect from the regulated party once we get further along in the inspection planning,” he said. “We expect personnel to be available and to respond to inspector requests once we start. Sometimes there might be delays, depending on how we are doing the remote inspection, on when documents are received. We make a ground rule that if the company cannot provide documents by a certain date, we consider them not to be available and potentially to be a deficiency.”

As of March 2020, Health Canada canceled all foreign inspections. In the interim, the agency is working with its international partners to ascertain industry compliance, including sharing inspection reports and keeping them informed of its current actions and approaches.

2019 Drug GMP Inspection Case Studies

Downing explained that the case studies he presented are all based on actual occurrences in 2019, i.e., pre-pandemic. The case studies cover:

  • An API rejected by an oral solid dosage (OSD) site due to the presence of metal particles
  • Observations made by inspectors discovered during the review of closed-circuit television (CCTV) footage
  • Data integrity issues discovered at an OTC topical liquid manufacturer

Case Study 1: Metal Particles in API

An API was returned due to metal particles found during the formulation step at an oral solid dosage site. The API manufacturer reprocessed it using the final isolation, drying, and milling steps that already existed using a reprocessing step in the manufacturing process, which is included in the master production documents.

The investigation was deficient. The nature of the contamination was never confirmed. It was assumed to be metal from damaged mill parts discovered later. The process capability of the purification was never assessed for metal. There was no assessment that the reprocessing steps for removal of related substances and particle size were suitable for the removal of the metal contamination.

Overall, agency investigators noted a deficient risk assessment with no consideration of using metal detectors resulting in no outcome. “In conclusion, rework is to be avoided. Contaminants are to be identified analytically and linked definitively to a source. Scientific rationale and process assessments are needed for any evidence of process capability. API manufacturers should be using metal detectors if the final step is milling,” Downing emphasized.

Case Study 2: GMP Inspectors Review CCTV Footage

An API manufacturer had visibly dirty equipment on inspection but had recently recorded a full cleaning performed two weeks earlier with no subsequent operations using that equipment. The inspector noticed that there were CCTV cameras present and reviewed the video for the day the cleaning was supposed to have taken place, and the video showed that equipment was not cleaned that day.

The review of the video also revealed that the interior of the facility was painted, including the cleanroom, milling, and packaging rooms, with no change control management.

“I find it interesting that the CCTV monitoring was a condition in the client’s quality agreement. If a company has a streaming CCTV in the control room, sitting down and looking at that is quite interesting because we can see how operations place, maybe unawares to the operators,” the Health Canada inspector said.

In conclusion, monitoring tools are being requested and used by inspectors as they become more familiar with electronic systems and ongoing surveillance. “And as I said, in Canada inspectors have been given new powers for remote access. We no longer have to be onsite to get the records in Canada.”

Case Study 3: Data Integrity Issues at OTC Manufacturer

An OTC topical liquid manufacturer had a large production office that exited into a packaging hall. During the inspection, the 12 office cubicles in that office were individually inspected. Each cubicle garbage can was emptied on the floor to reveal numerous handwritten documents. And of interest were several instrument printouts with numerical values and times. The company did not have any written governance for the destruction of signed production and packaging documents.

“This puts the company in a real bind, because how does it explain all the ripped printouts?” Downing asked. “It was exceedingly difficult for the company to explain each item found in the trash due to the sheer number and condition of the documents. So, something to be mindful of is good documentation practices, especially in the GMP production area.”

“In conclusion, there is no freedom in a GMP environment. Every attempt at a significant GMP activity needs an appropriate record that is controlled through its life cycle by a document management process. Non-GMP activities and recordkeeping should be kept to an absolute minimum in a production office in a controlled GMP area,” the Health Canada ROEB inspector stressed.

[Related: Download a special report covering the state of remote inspections FY2020, including a look at how virtual reality could be integrated into a remote inspection.]

Jerry Virtual report

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