Manufacturing Control - C.02.011 & C.02.012
Q.1 Can a single lot number be assigned to two or more co-mingled lots of bulk finished drug products packaged during the same run?
A.1 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) require that each batch must be identified by an individually numbered manufacturing batch document, each lot or batch of the finished product shall be fully tested against the specification and retained samples for each lot or batch shall be kept. Packaging of multiple lots of bulk finished drug product in a single packaging run with one lot number should be done only in exceptional circumstances and should be well documented with appropriate justification. The shortest expiry date of all the lots packaged must be indicated on the label. In case of a product recall, the company must recall the entire lot comprising all the sub-lots.
Q.2 What is the acceptable deviation in physical counts of finished product stock?
A.2 The allowable deviation between physical counts versus counts as per records (including computer records) should be zero. All finished product stock must be fully accounted for and records of distribution
and disposition must be maintained. Any deviations from physical counts versus expected counts as per the records, should be investigated and the results of such investigations should be documented.
Q.3 When are independent checks by another operator necessary?
A.3 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) indicate that a number of measures be taken to maintain the integrity of a drug product from the moment the various relevant raw materials enter the plant to the time the finished dosage form is released for sale. These measures seek to eliminate as many sources of error as possible so that only those drugs which have met established specifications are distributed.
One of the approaches proposed to achieve this goal is to have written procedures that ensure that each ingredient added to a batch is subjected to one or more checks for identity and quantity by qualified personnel.
If by its design, construction, operations and security features the procedure is such that the company assures that it is impossible to make an error, an independent check by another operator may not be considered necessary.
Checks for identity and quantity of dispensed materials also require independent checks by a second individual.
However, independent checks that materials have been added to the batch have traditionally been assumed to take place at the time of actual addition of the materials.
Other means of verifying the addition of materials may be considered. One alternative involves checking staged materials in the immediate compounding area prior to starting processing and then afterwards, verifying the empty containers before clearing the compounding area. This would be in conjunction with the use of individual processing rooms, otherwise we would need to be satisfied that there was very good separation of compounding operations.
Q.4 What are the expectations on label accountability?
A.4 It is expected that sufficient controls are in place to ensure that correct labels are applied during a labelling operation and that printed packaging materials are accounted for.
One acceptable means of meeting this requirement is to issue an accurately counted number of labels. That number should be reconciled with the number of labels used, damaged and returned to stock.
In theory, the target set in your procedure should be “0" deviation for labels and other printed packaging materials. Any significant or unusual discrepancy observed during reconciliation of the amount of bulk product and printed packaging materials and the number of units packaged is investigated and satisfactorily accounted for before release.
Q.5 Is verification of empty containers an acceptable check for addition of ingredients?
A.5 Yes. It is acceptable to check staged materials prior to and after processing as a method of checks for addition through verification of empty containers.
The preferred method for conducting addition checks is by direct observation by the verifier. The verification of empty containers is an acceptable alternative, but only where stringent controls exist regarding the
handling of dispensed raw materials.
Such controls include:
-assurance that a dispensed raw material does not end up in the wrong batch; locked portable cages are being used by some firms and only pertinent cages are permitted in the room at the same time.
-adequate operator awareness, training and motivation; the operator has to assure that additions are performed in the proper sequence; any spillage of raw materials must be promptly reported.
-pre and post checking should be performed by qualified personnel and whenever possible should be the same person.
-the post processing check must be performed prior to removal of any material from the area.
Q.6 Are quarantine and release stickers required on all containers of raw materials and packaging materials?
A.6 Quarantine and release stickers are required on all containers of raw materials and packaging components to identify status when a physical quarantine/release system is used.
However, such stickers are not required when a validated electronic quarantine system which effectively prevents the possibility of inadvertent use of unreleased material is in place.
When fully computerized storage systems are used, backup systems should be available in case of system failure.
Q.7 Is an answering machine acceptable for recall activation outside normal working hours?
A.7 A telephone answering machine may be used as part of the provisions for off-hours product recall activation. It should provide information on who to contact, their phone numbers, etc. Its use, functions and monitoring requirements should be included in the written procedures.
Q.8 Is it necessary to document quantities by lot numbers of finished stock destroyed?
A.8 For products returned to the distributor’s facility for destruction due to reasons such as damaged or expired product, it may not be mandatory to document the quantities destroyed by lot number.
For products returned following a recall, it is mandatory to document the returns by lot number as it is a requirement to perform a final reconciliation.
If an establishment recall procedures depend on dates of first and last sale of a given lot, records of destruction by lot numbers may provide necessary information pertaining to accountability per lot.
Q.9 Is there a standard on what should be stated in a recall procedure? (Updated)
A.9 Section C.02.012(1)(a) of the Food and Drug Regulations requires that every fabricator, packager/labeller, distributor, importer, and wholesaler of a drug maintains a system of control that permits complete and rapid recall of any lot of batch of the drug that is on the market. Such a system must be tailored to an individual organization and operation.
A written recall system should be in place to ensure compliance with Section C.01.051 of the Food and Drug Regulations and should include the requirements outlined in Interpretations 1.1 to 1.11 under Section C.02.012 Manufacturing Control of the “Goo d Ma nuf act uri ng Practices Gui del ines, 200 9 Ed ition (G UI-
0001)” (http://www.hc-sc.gc.ca/dhp-mps/compli-conform/gmp-bpf/docs/gui-0001-eng.php). Additional information is available in the “Recall Policy (POL-0016)”
(http://www.hc-sc.gc.ca/dhp-mps/compli-conform/info-prod/drugs-drogues/pol_0016_recall_policy-politique
_retrait_ltr-doc-eng.php) and the document entitled “Product Recall Procedures”
(http://www.hc-sc.gc.ca/dhp-mps/compli-conform/recall-retrait/recall_proc-marche_retrait-eng.php).
Q.10 Under what circumstances must one initiate a recall?
A.10 Please refer to the “Recall Policy (POL-0016)”
(http://www.hc-sc.gc.ca/dhp-mps/compli-conform/info-prod/drugs-drogues/pol_0016_recall_policy-politique
_retrait_ltr-doc-eng.php) and the document entitled “Product Recall Procedures”
(http://www.hc-sc.gc.ca/dhp-mps/compli-conform/recall-retrait/recall_proc-marche_retrait-eng.php).
Q.11 May firms omit second person component weight check if scales are connected to a computer system?
A.11 No, for an automated system that do not include checks on component quality control release status and proper identification of containers.
Yes, for a validated automated system with bar code reader that registers the raw materials identification, lot number and expiry date and that is integrated with the recorded accurate weight data.
Q.12 For a contract fabricator, is it a requirement to test the raw materials offered by customers?
A.12 Testing of raw materials (RM) is a responsibility of the fabricator. Therefore, an observation will be made to a fabricator for not testing a particular RM (even when this RM is provided by the client) if he is not excluded by his client according to a contract. Interpretation 3.2 under Section C.02.012 Manufacturing Control covers the written agreements with regard to the fabrication, and packaging/labelling among the parties involved, and Interpretation 6.10 under Section C.02.015 Quality Control Department covers the written agreements with regard to the testing among the parties involved. If no such agreement is in place, the observation will be made against the party responsible according to the Good Manufacturing Practices.
Q.13 If the customer asks a contract fabricator not to test a finished product, is it necessary for the contract fabricator to test the product?
A.13 Interpretation 3.2 under Section C.02.012 Manufacturing Control covers the written agreements with regard to the fabrication, and packaging/labelling among the parties involved, and Interpretation 6.10 under
Section C.02.015 Quality Control Department covers the written agreements with regard to the testing among the parties involved. If no such agreement is in place, the observation will be made against the party responsible according to the Good Manufacturing Practices.
Q.14 Is a contract fabricator or packager responsible for qualification of utilities and systems and cleaning validation or is it the responsibility of the distributor? And what about the validation of the manufacturing/packaging process and test methods?
A.14 The contract fabricator is responsible for the qualification of utilities and systems and cleaning validation as those requirements are not product specific.
For process validation and test method validation, the main responsibility rests with the distributor, according to Section C.02.003 of the Food and Drug Regulations. The contract fabricator, packager or tester retains responsibility in terms of process or test methods validation unless a written agreement is signed by both parties that excludes the responsibility of the contract fabricator, packager or tester to perform validation activities.
Q.15 How long in advance can the raw materials be weighed?
A.15 It is acceptable to weigh the raw material (RM) in advance of the scheduled date of production. However, the firm should be able to demonstrate that the materials and design of the containers in which the RM are weighed and kept will not alter their quality, the characteristics of the RM must also be taken into consideration. Interpretation 2 of Section C.02.026 Samples may provide guidance to this effect. Pre-weighed material should be appropriately labelled to ensure traceability. A system should be in place to ensure that
the material is still suitable for use on the date of manufacturing.
Q.16 If a licensed packager/labeller is packaging a drug for a foreign establishment which is not intended to be sold in Canada as described under Section 1.0 of "Conditions for Provision of Packaging/Labelling Services for Drugs under Foreign Ownership (GUI-0067)"
(http://www.hc-sc.gc.ca/dhp-mps/compli-conform/gmp-bpf/docs/gui_67-eng.php), should this foreign site be listed on the licence of the packager/labeller?
A.16 No. Since this drug would not be sold by the packager/labeller, this establishment would not be considered as an importer under Division 1A of the Food and Drug Regulations and thus, this site would not have to be listed on the licence of the packager/labeller. However, the packager/labeller would still need to fulfil all the requirements outlined under Section 4.0 of GUI-0067 that is: obtaining evidence of GMP compliance of the foreign site and supplying the proper information to Health Canada within the prescribed time frame.