CHAPTER 12

QUALITY CONTROL

REF

WHO 32

YES

NO

1

Section 3.2

Does the Quality Control laboratory carry out its own:

1.1

Section 3.2

Physicochemical controls?

1.2

Section 3.2

Microbiological controls?

1.3

Section 3.2

Biological controls?

2

Section 14.1

Is a clearly defined flow of samples and documentation established?

3

Section 11.29

Are the physicochemical and microbiological controls sector physically separated?

4

Sections18.46;

16.1 and 3.2g

Is the Quality Control Department responsible for approving or rejecting the raw materials, packaging materials, intermediate products, and finished products?

5

Section 3.2

Is there personnel with assigned responsibility to inspect the manufacture processes (own and in third parties)?

6

Sections 11.30 and

12.1

Are the installations and the equipment as appropriate with the type of manufacture?

Are the installations and the equipment as appropriate for the type of active ingredients handled?

7

Is there a defined area for the washing and conditioning of materials exclusively destined for the physicochemical laboratory?

8

Are there safety installations such as shower, eye washer, fire extinguisher, and protection elements?

REF

WHO 32

QUALITY CONTROL

YES

NO

8.1

Is there an operation verification program for the safety equipment?

8.2

Are the records kept?

9

Section

18.47

Is there the necessary equipment for the analytical controls required for materials and products?

Attach list of equipment

10

Sections 8.1; 8.9; 8.10; 8.11

and 8.12

Are there tests that because of their dangerousness and/or grade of complexity of the determination and/or very low frequency, becomes necessary the contracting of an external service?

10.1

Sections8.1; 8.9; 8.10; 8.11 y

8.12

Are these tests performed by contracted laboratories or by agreements with official laboratories?

10.2

Sections 8.1; 8.9; 8.10; 8.11

and 8.12

What are the tests carried out in these laboratories?

10.3

Sections 8.1; 8.9; 8.10; 8.11

and 8.12

Are there technical contracts/agreements?

10.4

Sections 8.1; 8.9; 8.10; 8.11

and 8.12

Does the contracted laboratory have all the technical information to perform the controls in total concordance with the techniques of control of the titular company?

10.5

Sections 8.1; 8.9; 8.10; 8.11

and 8.12

Does the Titular Company's Quality Control Laboratory receive from the Contracted Laboratory the results of the tests?

10.6

Sections 8.1; 8.9; 8.10; 8.11 and 8.12

Does the Titular Company's Quality Control Laboratory have access to all the data in order to confirm these results?

11

Is there a program for preventive maintenance for all the equipment?

REF

WHO 32

QUALITY CONTROL

YES

NO

11.1

Are there records that shown preventive maintenance program compliance?

12

Section 17.32

Is there a program of equipment calibration?

12.1

Section 17.32

In the equipment calibration program is indicated, which operations are performed internally and which by contracted services?

12.2

Section 17.32

Is the frequency of calibration indicated in the equipment calibration program?

12.3

Section 17.32

Are records of calibration of each equipment that shown program compliance?

13

Section 17.32

Are there written procedures to perform the calibration of each equipment?

14

Section 17.32

Do the calibration certificates or reports indicate the traceability to standards?

14.1

Section 17.32

Do the calibration certificates or reports indicate the uncertainty of the corresponding measure?

15

Section 17.32

Is the equipment correctly labeled indicating the calibration validity?

16

Section 17.32

In case of internal calibrations, does the laboratory have certified standards?

17

Section 17.32

Are the corresponding certificates shown?

18

Does the laboratory have procedures for the performance qualification (PQ) of equipment?

18.1

Is there documentation that endorses the fulfillment of this procedure?

19

Sections3,2(b);

3.2(h); 16.2

and 16.7

Are there SOPs with the detailed description for the sampling of:

REF

WHO 32

QUALITY CONTROL

YES

NO

19.1

Sections3,2(b);

3.2(h); 16.2

and 16.7

a) Raw materials?

19.2

Sections3,2(b);

3.2(h); 16.2

and 16.7

b) Packaging materials?

19.3

Sections 3,2b; 3.2(h); 16.2 and

16.7

c) Intermediate product?

19.4

Sections3,2(b);

3.2(h); 16.2

and 16.7

d) Finished product?

20

Section 16.3

Are the sampling methods for tests representative of the totality of the lot or batch?

20.1

Section 16.3

Are these procedures fulfilled?

21

Sections

13.11 y 16.9.

Are the sampled containers correctly analyzed and identified?

22

Sections 13.11;

16.9 y 16.7

Does the number of sampled containers agree with the sampling standard?

23

Sections

14.37(a); 16.3 and 16.8

Are all incoming packaging materials, without exception, sampled by Quality Control in accordance with the established standard?

24

Is there a SOP for the approval and rejection of the materials?

25

Section 16.5

Are there the elements necessary for the sampling?

25.1

Section 16.5

Are the sampling elements conserved in good condition?

25.2

Section 16.6

Are the sampling elements duly stored and labeled?

25.3

Section 16.6

Is there a written procedure for the cleaning, use, and conservation of the sampling elements?

REF

WHO 32

QUALITY CONTROL

YES

NO

26

Section 3.2

Are the analytical methods utilized authorized by the one responsible of Quality Control?

27

Is there a program for validation for the methods that are not published in pharmacopoeias internationally recognized?

27.1

Is there a record of compliance with that validation program?

28

Sections 3.1;3.2;

14.13 and 14.18

Are there specifications for:

28.1

Section 16.8

Raw materials?

28.2

Section 16.8

Packaging materials?

28.3

Section3.2

Intermediate product?

28.4

Section 16.13

Finished product?

29

Section 13.19

Are there SOPs that indicate the frequency of re-analysis and the validity of the carried out tests?

29-1

Are these procedures fulfilled?

30

Section 3.2(h)

Are samples of retention of the active raw materials and finished products, in enough quantity to carry out all the tests by duplicate, kept in accordance to a SOP?

31

Section 16.16

Are the retention samples of finished products kept until a year after the expiry date of the product?

31.1

Section 16.16

Are the samples of retention of raw materials kept until a year after the expiry date of the last lot of product prepared with them?

32

Section13.34

Are there standards and reference materials?

32.1

Section 14.12

Is a record of the primary standards kept?

REF

WHO 32

QUALITY CONTROL

YES

NO

32.2

Section 14.12

Is a record of the secondary standards kept?

32.3

Section 14.12

Is a record of the reference materials kept?

33

Section13.36

Does the company have primary standards, coded by Pharmacopoeias or internationally recognized agencies, for each active ingredient?

33.1

Section 14.12

Are the primary standards from the current lot?

34

Section 14.12

Do all the secondary standards and reference materials have current analytical certificate?

35

Section 13.36

Are there SOPs for the preparation, use and conservation of standards and reference materials?

35.1

Are those procedures fulfilled?

35.2

Section 13.36

Are the records shown?

36

Section 13.36

Are tests of characterization and purity carried out to the samples to be utilized as reference substances of non-coded active ingredient?

37

Does the company have impurities and related substances standards, officials or non-officials, especially for those considered toxic?

38

Section 3.2

Does the company have all the reagents needed for carried out the routine physicochemical assays?

38.1

Section 3.2

Are the reagents correctly labeled?

39

Section 13.32

Are volumetric solutions used?

39.1

Section 13.32

Is there a standard operating procedure for the preparation, use, and,conservation of volumetric solutions?

40

Section 13.32

Do every container of analytical solution have a label where there is indicated:

REF

WHO 32

QUALITY CONTROL

YES

NO

40.1

Section 13.32

Name of the solution?

40.2

Section 13.32

Concentration - standardization factor?

40.3

Section 13.32

Preparation date?

40.4

Section  13.32

Responsible?

40.5

Section 13.32

Retest date?

40.6

Section 13.32

Expiry date?

40.7

Section13.32

Storage conditions?

40.8

Section 13.32

Safety category?

40.9

Section 13.32

Reference to the SOP?

41

Section 13.32

Are the unstable reagents labeled with reception date, opening date and expiry date?

42

Sections 3.2.3 and 14.9

Do the analysts have a logbook in which are recorded the laboratory results?

43

Are the calculations dated and signed by the analyst?

44

Section 14.43

If there are observed modifications of data, is the amendment carried out dated and signed?

Does the amendment make possible to visualize the original datum?

45

In the records of the analyses, it is indicated:

45.1

Name of the analyzed material?

45.2

Lot number?

45.3

Analysis number?

45.4

Obtained results?

45.5

Date?

REF

WHO 32

QUALITY CONTROL

YES

NO

45.6

Utilized methods and specifications?

45.7

Signs/ initials of the people who carried out the test?

45.8

Sign/initials of the person that verified the tests and calculations?

45.9

In case of having computerized systems for the acquisition of data, do they make it possible to be confirmed?

46

Does Quality control check if each manufactured lot meets the established specifications?

46.1

Are there records?

46.2

Are the causes of the out of specifications results investigated?

46.3

Are there records of this investigation?

46.4

Are there records of the actions taken in those cases?

47

Does the records of the tests contain at least the following information:

47.1

Sample identification?

47.2

Date?

47.3

Name of the analyst?

47.4

Identification of the reference standard?

47.5

Parameters and conditions that correspond?

48

Section 17.90

Are tests of bacterial endotoxins carried out in raw materials and goods declared as pyrogen-free by the supplier, to be used in the injection manufacture?

REF

WHO 32

QUALITY CONTROL

YES

NO

49

Section 17.90

Are tests of pyrogens or bacterial endotoxins carried out in the finished products for injection, when it corresponds?

50

Section 17.90

Is an official method utilized for bacterial endotoxin control?

51

Section17.90

Otherwise, is the method validated?

52

Are pyrogen tests carried out in animals?

52.1

If "YES":

52.2

Section 11.10

Does the company have its animal house?

52.3

Does the company use a contracted animal house?

52.4

In any of both cases, does animal house fulfills with the current regulations on animal operation and management?

52.5

Section 11.10

If the company have animal house, is this separated from the other installations?

53

Are microbiological controls carried out?

54

Section 11.29

Does the company have separated areas for sterility test and other microbiological controls?

55

11.31

Are there proper areas and laminar flow for carry out the sterility tests?

56

Section 17.32

Are the filters of the laminar flow periodically checked?

57

Section 13.31

Does the company have the materials, culture media and reagents necessary for carrying out the routine microbiological controls?

57.1

Section 13.32

Are the materials, culture media and reagents within the validity period?

REF

WHO 32

QUALITY CONTROL

YES

NO

58

Section 13.32

Are the dehydrated culture media stored in the conditions of humidity and temperature indicated by the manufacturer?

59

Are the parameters of every sterilization cycle of culture media recorded?

60

Section 13.33

Is the growth promotion test carried out whenever new lots of culture media are utilized?

61

Section 13.32

Is a standard operating procedure for the preparation of culture media?

62

Sections14.12;

13.31; 13.34

and 13.32

Are microbial reference strains?

62.1

If there are reference strains, are they certified by an internationally recognized agency?

62.2

Is there a record of identification and use of strains?

62.3

Is the transfer frequency established?

62.4

Are the transfers recorded?

62.5

Are periodic controls carried out in order to confirm the viability?

62.5.1

Are periodic controls carried out in order to confirm the morphological and biochemical identity?

63

Section 17.87

Are sterility tests carried out?

63.1

Sections 17.90

y 3.2 (c)

For sterility tests, are coded methods utilized?

63.2

Section 3.2 (c)

Otherwise, is the method utilized for sterility tests validated?

64

Section 17.89

Is there a record of % of false positive?

REF

WHO 32

QUALITY CONTROL

YES

NO

64.1

Is the % of false positive not more than 0.5 % from total?

65

Which is the culture utilized for the sterility test?

65.1

If the lot fails the sterility test, is a complete investigation of the causes made?

65.2

Is a second test carried out if only if it demonstrated that the original test was not valid?

66

Are antibiotic potency assays carried out?

66.1

Is the statistical proof of the determination of potency and validity of the test carried out?

67

Section

11.29

Does the company have areas or sectors assigned for the sample

preparation?

67.1

Section 11.29

Does the company have areas or sectors assigned for the washing and conditioning of materials?

67.2

Section 11.29

Does the company have areas or sectors assigned for the preparation of culture media?

68

Sections 12.1 and 12.2

Does microbiology sector have equipment for bacterial decontamination?

69

Is there a procedure for the handling and disposal of chemical and microbial waste?

69.1

Does the procedure indicate that should not be permitted the accumulation of discarded materials?

69.2

Are the discarded materials eliminated safely and sanitarily at regular and frequent intervals?

70

Does Quality control carries out environmental microbiological controls?

70.1

Are there records?