Packaging Material Testing - C.02.016 & C.02.017
Q.1 What is the Inspectorate’s position on 2-mercaptobenzothiazole (MBT) in rubber closures?
A.1 MBT is sometimes used in the manufacture of rubber stoppers used as closures for vials or as components of syringes. Due to the concerns about the potential toxicity of MBT, its use in the manufacture of packaging materials that are in direct contact with injectable drugs is not permitted.
Q.2 Is it necessary to include a chemical identification test in a specification for a packaging component (such as a plastic bottle)? Must this chemical identification (ID) be conducted for each lot received? Would vendor certification be considered an acceptable substitution for testing upon receipt?
A.2 If the type of material is described on the Certificate of Analysis (C of A) and if a specific test has been performed by the fabricator of the packaging materials confirming the identity of the starting polymer used to manufacture a specific lot, it is not necessary to repeat the chemical ID (such as Infra-Red). But each lot of packaging materials should be visually examined to confirm the identity.
Q.3 Can industrial grade nitrogen be used as a blanketing agent during the manufacture of a drug product?
A.3 No. Any gas used as a blanketing agent should be of compendial standard.
Finished Product Testing - C.02.018 & C.02.019
Q.1 Do bacteriostasis and fungistasis testing have to be performed for each lot of product in reference to the United States Pharmacopoeia (USP) sterility test?
A.1 No. This needs to be established only once for a specific formulation to determine the suitable level of inoculate for that product. If the formulation has not changed for a number of years, periodic verification can be done as microorganisms become resistant to preservatives in a formulation.
Q.2 Does the Inspectorate encourage the use of environmental isolates for preservative effectiveness testing?
A.2 While the use of environmental isolates in addition to the specified compendia cultures is acceptable, the use of environmental isolates alone is not acceptable.
Q.3 What are the Inspectorate’s expectations for process parametric release for foreign and Canadian manufacturers?
A.3 Further information is available in the document entitled “Annex 17 of the Current Edition of the Good
Manufacturing Practices Guidelines - Guidance on Parametric Release (GUI-0046)”
(http://www.hc-sc.gc.ca/dhp-mps/compli-conform/int/part/gui_0046_tc-tm-eng.php). Please note that requests will be considered only for terminally sterilized drugs in their immediate containers and following
submission and approval of evidence acceptable according to this guidance.
Q.4 Should an inspector observe and question a technician’s analytical work?
A.4 An inspector may verify if the laboratory staff is qualified to carry out the work they undertake. This could occasionally include the observation of what the laboratory technicians are performing and question their actual analytical work in conjunction with standard operating procedures (SOP), methods or equipment used.
Also, inspectors will frequently examine testing data from the laboratory for format, accuracy, completeness, and adherence to written procedures. These matters would usually be regarded as requirements under Section C.02.015 Quality Control Department. The general requirements are outlined in Interpretation 6. Laboratory supervisors must sign off subordinates work as per Interpretation 6.3.
Q.5 Does the official method DO-25 apply to tablets labelled as being professed or as manufacturer’s standard?
A.5 Section C.01.015 of the Food and Drug Regulations specifies requirements relating to tablet disintegration times. These regulations require that all drugs in tablet form, intended to be swallowed whole, disintegrate in not more than 60 minutes when tested by the official method.
The regulations also prescribe a specific disintegration requirement and test for tablets which are enteric coated. Subsection (2) specifies conditions where subsection (1) requirements for DO-25 are not required, i.e., (e) drug demonstrated by an acceptable method to be available to the body, and (f) tablets which are for example extended release. Refer to C.01.011 and C.01.012.
The Inspectorate has no objection to the use of an alternate disintegration or dissolution method to demonstrate compliance with the prescribed release requirements provided that the method had been properly validated. It is understood the DO-25 is not generally used for new drugs.
Q.6 Do tests for impurities have to be repeated for finished products if they have been done on the raw materials?
A.6 The sponsor may have evidence that a related impurity present in the drug product is a previously identified/qualified synthetic impurity. In this case, no further qualification for that impurity is required at the drug product stage. The concentration reported for the established synthetic impurity may be excluded from the calculation of the total degradation products in the drug product, and should be clearly indicated as such
in the drug product specifications. Evidence should be provided in the submission demonstrating the related impurity is indeed a synthetic impurity (e.g., by showing constant levels during accelerated and/or shelf-life stability studies and confirmation by providing chromatograms of spiked samples). In cases where the methodology applied to the drug substance and drug product differs, the claim should be confirmed by appropriate studies and the results submitted (e.g., using actual reference standards for that compound).
For further information regarding the control of impurities, please consult Impurities in New Drug Substances
- ICH Q3A (R)
(http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/ich/qual/q3a(r)-eng.php) and
Impurities in New Drug Products - ICH Q3B (R)
(http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/ich/qual/q3b(r)-eng.php).
Q.7 What are the minimum testing requirements for solid dosage drugs?
A.7 The testing requirements for solid dosage form products include description, identification, purity, and potency and other applicable quality tests depending on the dosage form (e.g., dissolution/disintegration/drug release, uniformity of dosage units, etc.).
For new drugs, the minimum testing requirements have to be approved by the review Directorates.
Q.8 What are the standards other than the United States Pharmacopoeia (USP) that have official status in Canada?
A.8 The acceptable standards are described in Schedule B of the Food and Drugs Act;
• European Pharmacopoeia (Ph.Eur.)
• Pharmacopée française (Ph.F.)
• Pharmacopoeia Internationalis (Ph.I.)
• The British Pharmacopoeia (B.P.)
• The Canadian Formulary (C.F.)
• The National Formulary (N.F.)
• The Pharmaceutical Codex: Principles and Practices of Pharmaceuticals
• The United States Pharmacopoeia (U.S.P.)
Trade standards are also acceptable under certain conditions.
Q.9 Should compendial test methods be validated?
A.9 Since compendial methods cannot encompass all possible formulations of a drug product, the applicability of a compendial method to a company’s particular formulation of a drug product must be demonstrated. It must be determined that there is nothing in the product that causes an interference with the compendial method or affects the performance of the method. It must also be established that the impurities that would be expected from the route of synthesis or formulation are controlled by the compendial method.
The main objective of validation of an analytical procedure is to demonstrate that the procedure is suitable for its intended purpose.
For guidance on validation of analytical procedures, please refer to Text on Validation of Analytical
Procedures - ICH Q2A
(http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/ich/qual/q2a-eng.php) and Validation of Analytical Procedures - ICH Q2B
(http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/ich/qual/q2b-eng.php).
Q.10 Must all identification tests stated in a compendial monograph be performed?
A.10 Yes, all tests stated in the monograph must be performed.
Q.11 Are solid dosage drugs exempted from dissolution testing if sold under a manufacturer’s standard?
A.11 No, solid dosage drugs should include a routine test for monitoring release characteristics (e.g., dissolution).
Q.12 Do products labelled as United States Pharmacopoeia (USP) have to be tested as per the USP test methods?
A.12 No. An alternate method can be used, but the distributor must demonstrate that USP drugs comply with
USP specifications when tested by USP methods. If an alternate method is used, it must be fully validated and results from a correlation study should be available.
Q.13 What should be the calibration frequency for a dissolution apparatus used with both baskets &
paddles?
A.13 The “Good Manufacturing Practices Guidelines, 2009 Edition (GUI-0001)”
(http://www.hc-sc.gc.ca/dhp-mps/compli-conform/gmp-bpf/docs/gui-0001-eng.php) call for equipment calibration at suitable intervals. Although specific time periods are not given, equipment should be calibrated at a frequency necessary to ensure reliable and reproducible results and covered in the firm’s standard operating procedures (SOP). The firm may consult the apparatus manufacturer’s manual for guidance. Historical or validation data may also be used by the firm to support an appropriate calibration frequency.
In case of any event that might change operating characteristics of equipment, such as maintenance or moving it, it should be calibrated as required.
Q.14 In performing system suitability as per United States Pharmacopoeia (USP) <621>, do all replicate injections have to be completed before any analyte sample injections are made?
A.14 No.
Q.15 Is routine product pH testing required for endotoxin (limulus amebocyte lysate - LAL) testing?
A.15 No, provided that the method is validated and the firm has not committed to such testing in a new drug submission.
Q.16 Is the use of recycled solvents for high performance liquid chromatography (HPLC) columns acceptable?
A.16 Yes, provided that appropriate validation studies have been performed.
Q.17 If one lot of a product made in a Mutual Recognition Agreement (MRA) country is split into two separate shipments, is it mandatory for the importer to obtain separate manufacturer’s batch certificate for each shipment?
A.17 No. However, the importer should demonstrate that the conditions of transportation and storage applicable to this product have been met for each shipment.
Q.18 Is it acceptable to perform the testing, including the potency, before packaging or is it mandatory to perform this testing after packaging?
A.18 Other than the Identity testing which must be performed after packaging, as per Interpretation 1 under C.02.019 Finished Product Testing, there is no specific requirement to perform the other tests after packaging including potency. In such cases, the manufacturing process must be validated to demonstrate that the packaging / filling operation does not alter the quality of the product (including potency). These validation data must also demonstrate that the homogeneity of a product is maintained by appropriate means throughout the entire filling process for dosage forms such as lotion, creams or other suspensions. For parenteral, ophthalmic, and other sterile products, at least identity and sterility testing must be performed on the product in the immediate final container.
For the requirement to perform the identity testing after packaging, the unique identifier principle can be used as long as the chemical / biological identity test has been performed after the unique identifier is applied to
the product.
Q.19 A product is manufactured in a non-Mutual Recognition Agreement (non-MRA) country, then shipped in bulk in a MRA country where it is packaged and tested before being released and exported to Canada. Would the testing exemption provided by Interpretation 4 under C.02.019 Finished Product Testing apply?
A.19 No.