Therapeutic Products Programme

Holland Cross, Tower B

2nd Floor, 1600 Scott Street
Address Locator # 3102D1
OTTAWA, Ontario
K1A 1B6
January 21, 2000
99-038626

To: Associations
I am pleased to inform you of the release of a draft
guidance document entitled: Risk Classification of GMP
Observations which have been developed by the Good
Manufacturing Practices Committee of the Therapeutic
Products Programme. This Guidance Document is now available
on the Therapeutic Products Programme (TPP) Website at:
www.hc-sc.gc.ca/hpb-dgps/therapeut
The intent of this document is to classify the
observations noted during establishment inspections
according to their risk / gravity and to identify situations
considered unacceptable to TPP that will likely generate a
rating of Non-Conformity following the inspection.
Comments or suggestions regarding the content of this
document should be addressed to Ms. France Dansereau in the
Bureau of Compliance and Enforcement, by telephone at (613)
957-1492, by fax at (613) 952-9805, or by e-mail at
france_dansereau@hc-sc.gc.ca, by March 1, 2000.
Original signed By
Dr. Robert Peterson
For

Dann M. Michols
Director General

Therapeutic Products Programme

ANNEX TO THE GMP GUIDELINES

Risk Classification of
Good Manufacturing Practices

Version Number
Date issued
Date of implementation

Draft
December 31st, 1999

Health Canada
Therapeutic Products Programme

Good Manufacturing Practices

Risk Classification of GMP Observations
TABLE OF CONTENTS

PURPOSE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
SCOPE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
DEFINITIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
PROCEDURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
APPENDIX 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
PREMISES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
EQUIPMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
PERSONNEL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
SANITATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
RAW MATERIAL TESTING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
MANUFACTURING CONTROL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
QUALITY CONTROL DEPARTMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
FINISHED PRODUCT TESTING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
RECORDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
STABILITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
STERILE PRODUCTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7
7
7
7
7
8
8
8
8
9
9
9

APPENDIX 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
PREMISES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
EQUIPMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
PERSONNEL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
SANITATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
RAW MATERIAL TESTING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
MANUFACTURING CONTROLS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
QUALITY CONTROL DEPARTMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
PACKAGING MATERIAL TESTING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
FINISHED PRODUCT TESTING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
RECORDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
SAMPLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
STABILITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
STERILE PRODUCTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

10
10
11
12
13
13
14
15
16
16
17
17
17
18

APPENDIX 3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
PREMISES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
EQUIPMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
PERSONNEL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
SANITATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
RAW MATERIAL TESTING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
MANUFACTURING CONTROL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
PACKAGING MATERIAL TESTING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
RECORDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
SAMPLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
STABILITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

19
19
19
19
20
20
20
20
21
21
21

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Health Canada
Therapeutic Products Programme
1.

2.

Good Manufacturing Practices

Risk Classification of GMP Observations

PURPOSE
1.1

To classify the observations noted during drug plant inspections according to their
gravity /risk.

1.2

To ensure uniformity among the inspectors of the Therapeutic Products Program

in the attribution of the rating following drug plant inspections.

1.3

To inform the industry of the situations that the TPP considers unacceptable and
that will generate a rating of Non-Conformity (NC) following an inspection.

BACKGROUND
During a drug plant inspection, deviations to the different interpretative sections of the Good
Manufacturing Practices (GMP) guidelines are noted by the inspector and these deviations
appear as observations in the inspection exit notice at the end of the inspection. A
judgement based on these observations is then made by the inspector and a rating of
conformity (C) or non-conformity (NC) is assigned. Attribution of a NC rating may have
serious financial consequences for a company, ranging from the implementation of
important corrective measures to the temporary suspension or termination of the
Establishment Licence (EL). Therefore, these situations of non-conformity have to be well
defined, unambiguous and directly supported by the applicable regulations.

3.

SCOPE
The definition of a drug in Canada covers a wide variety of products ranging from
pharmaceuticals to biologics as well as Natural Health Products such as homeopathics and
herbal preparations. This guideline covers all such products to which Division 2 of Part C
of the regulations applies. However, as mentioned in the introduction to the 1998 edition
of the GMP guidelines, the evaluation of the conformity to the GMPs will be commensurate
with the risk involved taking into account the nature and extent of the deviation in relation
with the category of products evaluated. Nonetheless, most of the situations involving
fraud, misrepresentation or falsification of products or data will generate a NC rating,
irrespective of the category of products involved.
The appendices attached to the present document describe the observations related to each
category of risk. Please note that the list of observations in each appendix is not exhaustive
and that additional observations may be added where appropriate.

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Health Canada
Therapeutic Products Programme
4.

Good Manufacturing Practices

Risk Classification of GMP Observations

DEFINITIONS
In addition to the definitions described below, other definitions described in SOP-0006 (GMP
inspection of drug establishment) may apply.
4.1

Observation
A deviation or deficiency to the GMP noted by an inspector during the inspection
of a drug establishment that is attached to the inspection summary of the firm in the
TPPIRS and that is confirmed in writing to the company in the exit notice at the end
of the inspection. The observations are classified as Critical, Major and Other and,
as described in the TPPIRS, are assigned a risk classification, ranging from 1 for
critical to 2 for major to 3 for other.

4.2

4.3

4.4

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Critical observation
4.2.1

Observation that is likely to result in a non-compliant product that may

present an immediate or latent health risk.

4.2.2

Appendix I is a list of observation that the TPP considers as Critical. Those

will be assigned a Risk 1 in the TPPIRS as well as any deviation that
involves fraud, misrepresentation, or falsification of product or data.

Major observation
4.3.1

Observation that may result in the production of a drug not consistently

meeting its marketing authorization.

4.3.2

Appendix 2 is a list of observations that are considered as Major and that

will be assigned a Risk 2 in the TPPIRS. Certain Risk 2 observations, if
widespread or found serious enough, may be evaluated as Risk 1. Those
are identified by the following sign: (8)

Other observation
4.4.1

Observation that cannot be classified as either Critical or Major but which

indicates a departure from the GMP.

4.4.2

Other observations are not listed as such (observations that are neither
critical or major are considered as other and will be assigned a Risk 3 in the
TPPIRS) but Appendix 3 contains a list of other observations that may be
raised to major depending of the situation.

Health Canada
Therapeutic Products Programme
4.5

Critical product
4.5.1

A critical product is one for which one or more of the following criteria
apply:
.
.
.
.

4.6

High risk products means products that may trigger a health risk even at
low levels, following cross-contamination. Those include but are not limited
to Penicillins and to certain cytotoxic and biological products.

PROCEDURE
5.1

Instructions for assigning the inspection rating

5.1.1

Winter 1999

narrow therapeutic window / high toxicity

uniqueness
significant therapeutic indication
complex manufacturing process

High risk products

4.6.1

5.0

Good Manufacturing Practices

Risk Classification of GMP Observations

Risk 1 observations
.

If one or more Risk 1 observation is noted during an inspection, the

situation is immediately brought to the attention of companys
officials and they are duly informed that this will likely result in the
attribution of a NC rating.

When faced with such situation, the inspector will inform his/her
superior and discuss the appropriate course of actions that should
be considered to address the situation. An action plan specifying
the corrective measures to be taken as well as the time frame
necessary to implement these actions will be requested within an
appropriate target date from the company. In such situations
where in the opinion of the inspector the resulting products present
an immediate significant health hazard, appropriate actions such
as seizure, voluntary detention or suspension or termination of
manufacturing activities will be implemented or requested
immediately.

If the management of the company wishes to dispute the results of

the inspection report, the dispute resolution and appeals
mechanism described in the GMP and EL Enforcement Directive
should be followed.

Health Canada
Therapeutic Products Programme
5.1.2

Good Manufacturing Practices

Risk Classification of GMP Observations

Risk 2 observations
Where an inspection generates Risk 2 deviations, a C rating will be
assigned in most situations. However, a NC rating could be attributed to
a company in the following situations:

5.1.3

When numerous Risk 2 observations are noted during an

inspection indicating that the company does not
significantly control its processes and operations.

Repetition of most Risk 2 observations noted during

previous inspections showing that the company did not
implement the corrective actions submitted following the
previous inspection or did not put in place adequate
preventive actions in a timely manner to avoid recurrence
of such deviations.

Risk 3 observations
A C rating will be assigned in all situations where Risk 3 observations are
noted.

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Health Canada
Therapeutic Products Programme

Good Manufacturing Practices

Risk Classification of GMP Observations

APPENDIX 1
RISK 1 OBSERVATIONS
REGULATION
PREMISES
C.02.004
1.

No or inadequate ventilation system to eliminate airborne contaminants generated during

fabrication with evidence of cross-contamination.

2.

Inadequate segregation of manufacturing or testing areas for high risk products from other
manufacturing areas.

EQUIPMENT
C.02.005
1.

Critical equipment does not operate within its specifications.

2.

Most of the equipment used for critical manufacturing operations not qualified after
December 31, 1999.

PERSONNEL
C.02.006
1.

Individuals in charge of QC/production for a manufacturer of critical products are not

qualified by education, training and experience.

SANITATION
C.02.007 and C.02.008
1.

Sanitation program not followed combined with dirty premises and equipment (evidence of
accumulation of residues/extraneous matter).

2.

Evidence of gross infestation.

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Health Canada
Therapeutic Products Programme

Good Manufacturing Practices

Risk Classification of GMP Observations

RAW MATERIAL TESTING

C.02.009 and C.02.010
1.

Falsification or misrepresentation of analytical results.

2.

Raw materials not tested to ensure compliance with their specifications.

MANUFACTURING CONTROL
C.02.011 and C.02.012
1.

No written Master Formulae or Master Formulae prepared/verified by unqualified personnel

and showing gross deviations or calculation errors.

2.

Falsification or misrepresentation of manufacturing and packaging orders (including

combination of batches without proper documentation).

3.

Most critical production processes not validated after December 31, 1999.

4.

Recall
4.1

Absence of recall procedure combined with distribution practices that would not
permit to adequately recall a product (distribution records unavailable or not kept).

4.2

Improper quarantine and disposal practices that would allow recalled/rejected units
to be returned for sale.

QUALITY CONTROL DEPARTMENT

C.02.013 to C.02.015
1.

No QC department available on site.

2.

QC department not an independent unit, lacking real decisional power, with evidence that
QC decisions are overruled by production department or management.

FINISHED PRODUCT TESTING

C.02.018 and C.02.019
1.

Products not tested before release for sale.

2.

Falsification or misrepresentation of testing results / forgery of Certificate of analysis.

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Health Canada
Therapeutic Products Programme

Good Manufacturing Practices

Risk Classification of GMP Observations

RECORDS
C.02.020 to C.02.024
1.

Absence of records for product(s)

2.

Falsification or misrepresentation of records.

STABILITY
C.02.027 and C.02.028
1.

No data available to establish the shelf-life of products.

2.

Falsification or misrepresentation of stability data / forgery of COA

STERILE PRODUCTS
C.02.029
1.

Critical sterilization cycles not validated.

2.

PW and WFI systems not validated with evidence of problems such as high
microbial/endotoxin counts.

3.

No media fill performed to demonstrate the validity of aseptic filling operations.

4.

Aseptic filling operations maintained following unsatisfactory results obtained from media
fills.

5.

Batches failing initial sterility test released for sale on the basis of a second test without
proper investigation.

Winter 1999

Health Canada
Therapeutic Products Programme

Good Manufacturing Practices

Risk Classification of GMP Observations

APPENDIX 2
RISK 2 OBSERVATIONS
REGULATION
PREMISES
C.02.004
1.

Malfunctioning of the ventilation system resulting in possible migration of materials between

manufacturing areas. (8)

2.

Accessory supplies (steam, air, nitrogen, dust collection, etc...) not qualified.

3.

HVAC and purified water system not qualified/T and humidity not controlled or monitored
where required ( ex. in warehouse for sensitive products without supporting stability data).

4.

Damages (holes, cracks or peeling paint) to walls / ceilings immediately adjacent or above
manufacturing areas or equipment where the product is exposed.

5.

Un-cleanable surfaces created by pipes, fixtures or ducks directly above products or

manufacturing equipment.

6.

Surfaces finish (floors, walls and ceilings) that do not permit effective cleaning.

7.

Unsealed porous finish in manufacturing areas with evidence of contamination (mildew,

mould, powder from previous productions, etc..)

8.

Insufficient manufacturing space that could lead to mix-ups.

9.

Physical and electronic quarantine accessible to unauthorized personnel / Physical

quarantine not well defined.

10.

No separate area/Insufficient precautions for Raw Materials sampling.

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Health Canada
Therapeutic Products Programme

Good Manufacturing Practices

Risk Classification of GMP Observations

EQUIPMENT
C.02.005
1.

Lack of maintenance resulting in equipment that does not operate within its
specifications.(8)

2.

CIP equipment not validated.

3.

Tanks for manufacturing of liquids and ointments not equipped with sanitary clamps.

4.

Stored equipment not protected from contamination.(8)

5.

Inappropriate equipment for production: surfaces porous and non-cleanable / material to

shed particles.(8)

6.

Evidence of contamination of products by foreign materials such as grease, oil, rust and
particles from the equipment.(8)

7.

No covers for tanks, hoppers or similar manufacturing equipment.

8.

No/inadequate precautions taken when equipment such as oven or autoclave contains more
than one product (possibility of cross-contamination or mix-ups).(8)

9.

Equipment location does not prevent cross-contamination for operations performed in

common area.(8)

10.

PW system not maintained or operated to provide water of adequate quality.

11.

Leaking gaskets.

12.

No calibration program for automatic, mechanical, electronic or measuring equipment/no

records maintained.

13.

No equipment usage logs.

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Therapeutic Products Programme

Good Manufacturing Practices

Risk Classification of GMP Observations

PERSONNEL
C.02.006
1.

Individuals in charge of QC/production for a manufacturer are not qualified by education,

training and experience.

2.

Delegation of duties for QC and manufacturing director to insufficiently qualified persons.

3.

Although academically qualified, insufficient practical experience for QC and manufacturing

director.

4.

Personnel in insufficient number for manufacturing and QC operations resulting in a high

probability of error. If for critical products (8)

5.

No/insufficient initial and continuing training program for personnel involved in

manufacturing with evidence of insufficient knowledge of the processes, no evaluation of
training, no record kept, no periodic review. If for critical products (8)

6.

Insufficient training/experience for individuals responsible for packaging operations.

7.

Inadequate number of personnel with the necessary qualifications.

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Therapeutic Products Programme

Good Manufacturing Practices

Risk Classification of GMP Observations

SANITATION
C.02.007 and C.02.008
1.

Sanitation program not in writing/incomplete but premises in acceptable state of cleanliness.

2.

No SOP for microbial/environmental monitoring, no action limits for areas where susceptible
products are manufactured (8).

3.

Cleaning procedure for production equipment not validated (including analytical methods).

4.

No/incomplete health and hygiene program.

RAW MATERIAL TESTING

C.02.009 and C.02.010
1.

Reduce testing program in place without any data to certify the vendors/suppliers.

2.

Incomplete SOP or data to certify vendors/suppliers, to address NC results and re-certify

the vendors.

3.

Incomplete testing of RM/Incomplete specifications.

4.

Production personnel do not respect the quarantine status of raw materials.

5.

Specifications not approved by QC.

6.

Test methods not validated.

7.

No stability consideration/no retesting after two years.

8.

No consideration for multiple receptions of the same lot/multiple lots comprising one
reception.

9.

No SOP for conditions of transportation and storage.

10.

No ID done after receipt/Testing fro identity not done on each containers after manipulation
or repackaging by third party.

11.

No system for notification of changes in specifications or process by the vendor.

12.

Certification of brokers or wholesalers allowed.

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Health Canada
Therapeutic Products Programme

Good Manufacturing Practices

Risk Classification of GMP Observations

MANUFACTURING CONTROLS
C.02.011 and C.02.012
1.

Absence of/incomplete SOPs for handling of materials and products.

2.

Incomplete validation studies/reports for critical processes (lack of evaluation/approval).

3.

Unapproved/undocumented major changes compared to Master Production Documents. (8)

4.

Deviations from instructions not documented/no final approval from QC.

5.

Discrepancies in yield or reconciliation following manufacturing and packaging not

investigated.(8)

6.

Absence of/non-validated changeover procedures for manufacturing of medicinal/nonmedicinal products.

7.

Purging between manufacturing/packaging of different products not covered by SOP/not

documented.

8.

No regular checks for measuring devices/no records.

9.

Lack of proper identification of in-process materials and production rooms resulting in a high
probability of mix-ups.(8)

10.

Inadequate labelling/storage of rejected materials and products.

11.

Bulk and in-process drugs, RM and PM not held in quarantine til release by QC.

12.

Inadequate checks for incoming materials/No investigation from QC on damaged

containers.

13.

Inadequate/inaccurate labelling of bulk/in-process drugs, RM and PM.

14.

RM dispensing not done by designated persons, according to an SOP.

15.

Master Formulae incomplete or showing inaccuracies in the processing operations.

16.

Changes in batch size not prepared/verified by qualified personnel.

17.

Inaccurate/incomplete information in manufacturing/packaging work orders.

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Therapeutic Products Programme

Good Manufacturing Practices

Risk Classification of GMP Observations

18.

Combination of batches without QC approval/not covered by SOP.

19.

Packaging operations not covered by written procedures / written procedures incomplete.

20.

Non-standard occurrences during packaging not investigated by authorized personnel.

21.

Inadequate control of coded and non-coded printed packaging material (including storage,
dispensing, printing, disposal).

22.

Incomplete recall procedure.

23.

No or inadequate self-inspection program/Program does not address all applicable sections

of GMPs/Records incomplete or not maintained.

24.

No/incomplete System to ensure GMP compliance of contractors and vendors.

QUALITY CONTROL DEPARTMENT

C.02.013 to C.02.015
1.

Inadequate facilities, personnel and testing equipment/lack of power to enter production

areas.(8)

2.

No SOPs approved and available for sampling, inspection and testing of materials.

3.

Products made available for sale without approval of QC department.

4.

Products released for sale by QC without proper verification of manufacturing and

packaging documentation (evaluation of deviations and borderline conformances not
properly investigated and documented).

5.

Raw materials/packaging materials used in production without prior approval of QC.

6.

Rejected batches reprocessed without approval of QC department.

7.

No system for complaint handling, returned goods or transportation conditions.

8.

SOPs covering operations that can affect the quality of a product such as transportation,
storage, etc...not approved by QC department.

9.

QC decisions not attested by signature/dated.

10.

No change control system.

11.

No system to ensure that the tests are performed by a competent laboratory.

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Health Canada
Therapeutic Products Programme

Good Manufacturing Practices

Risk Classification of GMP Observations

PACKAGING MATERIAL TESTING

C.02.016 and C.02.017
1.

Reduce testing program in place without any data to certify the vendors/suppliers.

2.

Incomplete SOP or data to certify vendors/suppliers, to address NC results, to re-certify the

vendors.

3.

Incomplete testing of PM/Incomplete specifications.

4.

Production personnel do not respect the quarantine status of PM.

5.

Specifications not approved by QC.

6.

No consideration for multiple lots comprising one reception.

7.

No ID done after receipt.

8.

Certification of brokers or wholesalers allowed.

FINISHED PRODUCT TESTING

C.02.018 and C.02.019
1.

Noncompliant products made available for sale without proper justification.(8)

2.

Incomplete/inadequate specifications.

3.

Incomplete testing.

4.

Test methods not validated.

5.

Reduce testing program in place without data to certify vendors.

6.

Incomplete SOP or data to certify vendors/suppliers, to address NC results, to re-certify the

vendors.

7.

No SOP for conditions of transportation and storage.

8.

Use of unique identifier principles not meeting the acceptable options described in the
interpretive document.(8)

Winter 1999

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Health Canada
Therapeutic Products Programme

Good Manufacturing Practices

Risk Classification of GMP Observations

RECORDS
C.02.020 to C.02.024
1.

Incomplete records/documentation for a product.

2.

Unavailability of documentation from suppliers in a timely manner.

SAMPLES
C.02.025 and C.02.026
1.

Retained samples not kept for products outside the scope of alternative sample retention
directive.

2.

Failure to submit retained samples within 48 hours when alternative sample retention
granted.

STABILITY
C.02.027 and C.02.028
1.

Insufficient number of lots/insufficient data (room T or accelerated) to establish shelf-life.

2.

No action taken following data showing that the products do not meet their specifications
prior the expiry date.

3.

No continuing stability program/no stability data available.

4.

No stability studies prior changes in manufacturing (formulation)/packaging materials.

5.

Testing methods not validated.

Winter 1999

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Health Canada
Therapeutic Products Programme

Good Manufacturing Practices

Risk Classification of GMP Observations

STERILE PRODUCTS
C.02.029
1.

Aqueous-based products not subject to terminal steam sterilisation without proper

justification.

2.

Inadequate room classification for processing/filling operations.

3.

Aseptic manufacturing suites under negative pressure compared to clean (C-D) areas.
Clean (C-D) areas under negative pressure to unclassified areas (8) .

4.

Insufficient number of samples for room classification/inadequate sampling methods.

5.

No environmental controls/No monitoring for viable microorganisms during filling.(8)

6.

Premises and equipment not designed or maintained to minimize contamination/generation

of particles.

7.

Inadequate maintenance of PW and WFI systems/Inadequate re-validation after

maintenance, up-grading, out-of-specs trends.

8.

Inadequate formation/training of personnel/clothing requirements.

9.

Sanitation/disinfection program incomplete.

10.

Inadequate SOPs/practices/precautions to minimize contamination or prevent mix-ups.

11.

Non-validated time interval between cleaning, sterilization, use of components, containers

and equipment.

12.

No consideration given to initial bioburden prior sterilization and no validated time limit
between start of manufacturing and sterilization or filtration.(8)

13.

No SOPs for media-fills/Insufficient number of units filled during media-fills.

14.

Inadequate inspection for particles and defects/No leak test for ampules.

15.

Samples for sterility not representative of the entire production/insufficient number of units.

Winter 1999

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Health Canada
Therapeutic Products Programme

Good Manufacturing Practices

Risk Classification of GMP Observations

APPENDIX 3
RISK 3 OBSERVATIONS
REGULATION
PREMISES
C.02.004
1.

Doors giving access to exterior from manufacturing and packaging areas used by personnel.

2.

Un-screened/Un-trapped floor drains.

3.

Outlets for liquids and gases not identified.

4.

Damages (holes, cracks or peeling paint) to surfaces not directly adjacent or above exposed
products.

5.

Insufficient lighting

6.

Non-production activities performed in production areas.

7.

Inadequate rest, change, wash-up and toilet facilities.

EQUIPMENT
C.02.005
1.

Insufficient distance between equipments and walls to permit cleaning.

2.

Base of immovable equipment not adequately sealed at points of contact.

3.

Fixed pipework not labelled to indicate contents and flow.

4.

Use of temporary devices for repair.

5.

Defective/unused equipment not removed/not labelled.

PERSONNEL
C.02.006
1.

No provision for consultants/outside contractors.

2.

No organization charts.

Winter 1999

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Health Canada
Therapeutic Products Programme

Good Manufacturing Practices

Risk Classification of GMP Observations

SANITATION
C.02.007 and C.02.008
1.

Incomplete records on the application of the sanitation program.

2.

Personnel responsible for the application of the cleaning procedures not identified.

3.

Sporadic dust/powder/residue noticed on some manufacturing areas/equipment.

4.

Health and hygiene programs not properly implemented or followed by employees.

RAW MATERIAL TESTING

C.02.009 and C.02.010
1.

Lots identified for confirmatory testing used in production prior QC approval.

MANUFACTURING CONTROL
C.02.011 and C.02.012
1.

Access to production areas not restricted to authorized personnel.

2.

Containers from which samples have been drawn not identified.

3.

Containers not cleaned upon receipt.

4.

Check samples returned to packaging line.

PACKAGING MATERIAL TESTING

C.02.016 and C.02.017
1.

No SOP for conditions of transportation and storage.

2.

Inadequate segregation of outdated / obsolete PM. No records of disposition

Winter 1999

20

Health Canada
Therapeutic Products Programme

Good Manufacturing Practices

Risk Classification of GMP Observations

RECORDS
C.02.020 to C.02.024
1.

Incomplete plans and specifications for the manufacturing buildings.

2.

Incomplete documentation pertaining to supervisory personnel.

3.

Insufficient retaining period for evidences and records to be maintained.

SAMPLES
C.02.025 and C.02.026
1.

Samples not available/not found for Raw Materials.

2.

Insufficient quantity.

3.

Improper storage conditions.

STABILITY
C.02.027 and C.02.028
1.

Insufficient number of lots in continuing stability program.

2.

Incomplete testing of parameters/insufficient quantities for complete testing.

3.

Testing schedule not followed.

4.

Inadequate conditions of storage.

Winter 1999

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