Annex 3A to the Good manufacturing practices guide - Schedule C drugs (GUI-0026): Guidance

On this page

• Premises
• Equipment
• Personnel
• Sanitation
• Raw material testing
• Manufacturing control
• Quality control department
• Packaging material testing
• Finished product testing
• Records
• Samples
• Stability
• Sterile products

For each of the following sections, Health Canada's interpretations of Part C, Division 2 of the Food and Drug Regulations (regulations) are provided. Unless otherwise noted, the following interpretations are in addition to those in the Good manufacturing practices guide for drug products (GUI-0001).

Premises

C.02.004

Ensure radiopharmaceuticals and radionuclide generators are fabricated, packaged/labelled, stored and tested in facilities that prevent the contamination of drugs with unwanted sources of radioactivity (such as radionuclidic and radiochemical contamination).

Identify facilities used for handling radioactivity and restrict access to authorized personnel involved in the process.

Ensure airflow patterns do not present a contamination risk, while providing the needed protection for the product during critical operations.

Use:

• positive pressure areas to process sterile products that are not radiolabelled
• negative pressure in specific areas at points of risk for exposure to radioactivity

Ensure air handling filtration units are dedicated to specific processing areas.

Surround the negative pressure areas or safety cabinets (such as a hot-cell and a total containment glove box) with area(s) with a positive pressure zone.

Equipment

C.02.005

Ensure radiopharmaceuticals and radionuclide generators are fabricated, packaged/labelled, stored and tested with equipment that prevents the contamination of drugs with unwanted sources of radioactivity (such as radionuclidic and radiochemical contamination).

• Dedicated equipment is recommended for campaign production, to minimize the risk of cross-contamination

Ensure radioactivity measuring equipment (such as radionuclide dose calibrators and gamma counters) is available for fabrication and control operations, and that these devices are:

• shielded or located to avoid any source of background radiation
• calibrated regularly for accuracy and precision by competent personnel (maintain corresponding records)
• subject to installation and operational qualification (document the equipment qualification)

Personnel

C.02.006

Ensure personnel working in areas where radioactive materials are handled (including those involved in cleaning and maintenance) are given specific radiation safety training in accordance with other applicable federal guidelines.

For more information on radiation safety, consult:

• Canadian Nuclear Safety Commission (CNSC) regulations and guidelines

Ensure personnel have appropriate training for handling radioactive materials.

Sanitation

C.02.007 and C.02.008

Ensure your sanitation program includes procedures and practices in accordance with other applicable federal guidelines.

For more information on radiation safety, consult:

• CNSC regulations and guidelines

Ensure environmental monitoring of work areas includes programs addressing radioactive, microbial and particulate matter contamination.

Ensure that health hazards posed by material and reagents used to manufacture radiopharmaceuticals and exposure to the products themselves is reflected in your environmental and personal protective procedures and controls.

• Enforce proper personnel gowning before entering the facility

Monitor staff involved in production, quality control and maintenance activities for possible contamination and/or radiation exposure.

Raw material testing

Ensure packages containing radioactive raw materials (such as Molybdenum 99) are initially processed on arrival in accordance with other applicable federal guidelines.

For more information on radiation safety, consult:

• CNSC regulations and guidelines

The main objective of subsection C.02.009 (1) is to confirm the identity and purity of raw materials before their use. However, a lot or batch of raw materials that contains a radionuclide with a short physical half-life which does not allow tests to be completed before use may be used to fabricate a drug before all tests are completed. The provision is that such testing should be completed as soon as possible.

• Usually a part of the premarket authorization review

Ensure that non-radioactive raw materials manufactured in-house have proper master production documents, including specifications, details of their method of manufacture and details of the controls used to ensure their suitability for use.

• Usually a part of the premarket authorization review

Manufacturing control

C.02.011 and C.02.012

Carry out checks on yields and reconcile quantities at appropriate stages of the process to ensure that yields are within acceptable limits.

• Does not apply to radiopharmaceuticals and radionuclide generators in cases where the radioactive components decay at a rate that makes this task unrealistic

Ensure all shielded containers are identified with the name of the contents and the batch or lot number at all times during processing.

Ensure the master formula for a packaged radiopharmaceutical drug also includes for each product, package size and type:

• specific activity and/or radioactive concentration (at calibration)
• total volume and radioactivity in the final container
• type of shielding

Quality control department

C.02.013 to C.02.015

Ensure the individual (or authorized alternate) making decisions about the release of a particular lot of raw material, packaging material or packaged Schedule C drug is not the person who fabricates, packages/labels or sells the same lot.

Hold all finished products in quarantine and identify with a quarantine status until released by the quality control department.

• Where sterility and/or endotoxin testing is conducted on specific lots of short-lived radiopharmaceuticals, you may release the lots before sterility and/or endotoxin testing is completed (to be completed as soon as possible)

Ensure radiopharmaceuticals are stored, transported and handled in strict compliance with the market authorization and other applicable federal guidelines.

Ensure a procedure is in place describing the measures to be taken in the event that unsatisfactory/out-of-specification test results are obtained for batches released before complete testing.

• Procedure must include provisions for the authorized person to report to the proper regulatory authority

Packaging material testing

C.02.016 and C.02.017

Conduct a full evaluation of the risks involved, including any possible deleterious effects on product integrity, before the reuse of lead shielding is allowed.

• Make sure specific provision is made for this in the premarket authorization

Conduct compatibility studies on all materials in direct contact with the drug.

• For example, vials and stoppers for drugs with no-carrier-added radionuclides

Finished product testing

C.02.018 and C.02.019

Ensure written specifications describe the drug in dosage form, including all properties and attributes (for example, total radioactivity, specific activity or radioactive concentration), together with tolerances.

• Include a description of all tests or analyses used to determine those properties and attributes (in enough detail to allow performance by qualified personnel)
• Ensure analyses include the monitoring of generator eluate

Conduct sterility and/or endotoxin tests on batches of short-lived radiopharmaceuticals according to finished product specifications.

• Such batches may be released before sterility and/or endotoxin testing are completed, provided:
  • the overall process has been validated in advance and
  • testing is completed as soon as possible

Test batches of radiopharmaceuticals containing radionuclides of long half-life for all test parameters before release (if time permits) to confirm that they meet finished product specifications.

Radiopharmaceuticals and radionuclide generators that have a useful life of no more than 30 days

Exemptions from confirmatory testing and identity testing apply to the packager/labeller, distributor or importer of radiopharmaceuticals and radionuclide generators that have a useful life of no more than 30 days. These exemptions apply if the packager/labeller, distributor or importer has evidence that the drug has been:

• tested against the specifications for that drug and
• transported or stored under conditions that will not adversely impact the drug's quality

Imported radiopharmaceuticals and radionuclide generators that have a useful life of no more than 30 days may be shipped directly to the point of use (such as nuclear medicine departments). Direct shipping facilitates access to these radiopharmaceuticals and radionuclide generators. It also minimizes the risk of potential exposure by keeping the distribution chain as lean as possible.

However, before importing the drug, the importer must:

• receive and review documentation that demonstrates that the drug complies with the specifications for that drug
• have measures in place to ensure that all requirements of the Food and Drug Regulations (FDR) for importing the drug are met
  • must identify roles and responsibilities and have appropriate quality agreements between all parties, including the foreign fabricator, importer and receiver of the product

For information on quality agreements, consult:

• Good manufacturing practices guide for drug products (GUI-0001), section C.02.012

The importer must release the product before it can be administered to the patient. Its release, along with certain other activities (for example, reviewing and approving specifications, shipping, storing documentation, other documentation), can be done remotely by the importer.

In some cases, the Canada Border Services Agency (CBSA) will refer a shipment to Health Canada to verify if the requirements for import are satisfied. We recommend that direct shipments be accompanied by the following information:

• a statement that the importer is shipping directly to the point of use and not to the importer's warehouse
• the invoice that includes the importer's drug establishment licence (DEL) number
• a copy of the importer's DEL

For more information on importing health products into Canada, consult:

• GUI-0117: Importing and exporting health products for commercial use

Records

C.02.020 to C.02.024

For imported Schedule C drugs, keep in Canada detailed summaries of marketing authorization for current fabrication, packaging, labelling and testing procedures.

Samples

C.02.025 and C.02.026

Fabricators of drugs must retain a sample of each lot or batch of radioactive raw material used to fabricate a drug for 3 months after this lot or batch is last used to fabricate the drug (unless otherwise specified in the fabricator's establishment licence).

• Conditions for specifying raw material sample retention requirements in the fabricator's establishment licence may be due to, for example, a short physical half-life, excessively small amounts of the raw material and high radiation exposure from the retention process
• These considerations should normally be addressed in a written request at the time of the premarket authorization, specific to a given product and based on appropriate justification

Distributors (referred to in paragraph C.01A.003(b)) and importers of a kit must retain in Canada a sample of each lot or batch of the packaged/labelled kit for at least 1 year after the kit label's expiration date.

• Unless otherwise specified in the distributor's or importer's establishment licence

Stability

Generate stability data for a drug before marketing and before making significant changes in formulation, fabrication procedures or packaging materials that may affect the drug's shelf life.

Any significant change in the source of radionuclide or packaging components will require repeat assessment of stability.

• Establish the shelf life of non-reconstituted kits from the date/time of fabrication of the kit
• Establish the shelf life of radiopharmaceuticals or generators from the date/time of fabrication or calibration
• Establish the shelf life of reconstituted kits from the time of radiolabelling or calibration
• Ensure the stability protocol is designed so that the data cover at least the highest specific activity, total radioactivity or radioactive concentration to be used for preparing the radiopharmaceutical
  • design assumes that the stability of the intermediate condition samples is represented
• Demonstrate the stability of reconstituted kits by performing reconstitution using the extremes of reconstitution conditions and performing tests for radiochemical purity/impurity, pH and appearance, both at the time of reconstitution and at the time of expiry of the reconstituted drug
  • if the reconstituted drug is to be transferred to a secondary container or syringe for storage or distribution, validate stability and/or compatibility in that container or syringe

Demonstrate the stability for the storage time in the second container if a drug is transferred to a second container.

• Determine the stability for the final packaged dosage form

Ensure stability data are available to support the labelled shelf life of the product in its final container.

Ensure stability data are available for radiopharmaceuticals supplied in multi-dose vials, to support that multiple penetrations of the vial do not adversely affect the stability of the drug up to its labelled shelf life.

Note: These stability requirements are subject to premarket authorization.

Sterile products

C.02.029

Manufacture radiopharmaceuticals in qualified aseptic systems that ensure a Grade A environment, such as unidirectional flow (laminar flow) cabinets or total containment glove boxes.

Activities performed in aseptic systems/areas may include:

• aseptic addition of a sterile diluent to a sterile vial using a syringe
• aseptic attachments of sterile components and devices, such as:
  • connecting a sterile syringe or a sterile filter device to a sterile needle
  • inserting a sterile needle through a sanitized stopper into a vial and any penetration of, or creating an open pathway into, a sealed container-closure system after filling, as might occur with some post-filling sampling techniques

Ensure air velocity in aseptic areas (for example, laminar flow hoods) is sufficient to sweep particulate matter away from the filling and closing area:

• whenever possible, make sure equipment configuration does not disrupt the laminar flow
• separate different areas in the fabricating process with physical barriers whenever possible and supplement these with partial physical barriers (for example, air curtains) where needed

Perform radiochemical synthesis and high-performance liquid chromatography (HPLC) purification in a hot-cell with a Grade B or C environment:

• the hot-cell should meet a high degree of air cleanliness with filter feed air and be placed in a room with air classification of at least Grade C
• all aseptic activities must be carried out in a Grade A environment

Take additional measures to minimize contamination in cases where terminal steam sterilization is not possible or practical (due to the short physical half-life of the radionuclide involved or the thermal instability of the drug). Measures may include using closed systems of fabrication and sterile filtration.

• Validate the equivalence of these measures and ensure subsequent filling operations (or any further operations involving the entry or opening of sterile closed containers) are performed under aseptic conditions