Questionnaire for preparing GMP-inspections

Here you will find answers to the following questions:

  • What questions are typically asked during inspections based on current rules and regulations?
  • Which reference documents (e.g. CFR, EU GMP Guideline, IPEC) comprise the GMP-requirement in question?

 

Supplier audits as well as inspections by the authorities are, in many regards, stressful situations for the auditee. There is generally a great deal hanging on the result of the inspection, whether it is an order from an important customer or approval for a new product. This means that all the members of staff involved in the inspection are under intense psychological pressure, which can make it difficult to present normally self-evident processes to the inspector in a comprehensible way and to answer questions fully and correctly.

Common concerns include the following:

  • Will we be able to provide the correct answers or explanations to the questions posed in spite of general nervousness?
  • Can we prove everything with documentary evidence?
  • Can we explain that (and how) our GMP or QA system works?
  • Is our GMP status adequate?
  • Will the staff make oversights because they feel watched or because they are scared to fail?
  • Will the inspectors set "traps"?
  • Will someone be caught out by their own reasoning because they want to make a particularly good impression?
  • How will we stand internally after the inspection, e.g. with regard to other departments?

Only thorough preparation can help to relieve these uncertainties and self-inspection can be an important element of this (chapter 18.E Self-inspection). The advantage of a self-inspection is that you can play with an open hand and any deficiencies that are recognised can be corrected immediately. The disadvantage is that an internal auditor is generally too familiar with the individual processes (even to the extent of wearing professional blinkers) and only uses the internal terminology.

This only reflects the reality of an inspection by the authorities or a customer to a limited degree: here, the auditee may find himself confronted with terms or questions that he had not considered in the same way. The generality of a question is often a worry: what is the meaning of "adequate water systems"? What is the inspector driving at when he asks about "suitable equipment" or "qualified personnel"? Even the terms used in the GMP rules and regulations do not always correspond to the expressions used in the company and can cause uncertainty: for example, if the "test procedures" are queried, does this mean the control procedures, the testing instructions, the testing plan, the analysis procedure, the IPC instructions, the calibration procedure or the stability plan? What does "process instruction" mean in a particular instance? The manufacturing formula in accordance with EU GMP, the processing instructions in accordance with EU GMP, the manufacturing description in accordance with CFR, the master production record in accordance with CFR, the batch production record in accordance with CRP or even an SOP?

Suppliers, in particular, who have generally structured their quality management system according to ISO 9000ff or recently ISO 9001, use very different terms than the GMP inspector of a customer, for example. How do "quality planning", "quality control", "quality assurance" and "quality improvement" translate into GMP terms? Is "OOS" concerned with quality fault management or remedial actions? Can SPC and the concept of validation be made consistent?

For suppliers, an aggravating factor is that they are often confronted with GMP requirements that the pharmaceutical customer has been only too eager to pass on to the supplier. However, on closer inspection, many of these customer requirements cannot be traced back to legal requirements because they only relate to pharmaceutical products and not to the active pharmaceutical ingredient, excipient, packaging material or item of equipment.

To prepare for such general questions, an external consultant can be appointed to carry out a mock inspection. On the one hand, this allows the "real situation" to be tested and, on the other hand, it allows any weaknesses to be identified which would not be obvious internally.

Alternatively or in addition to this, it is worth using checklists to deal with the questions that a GMP inspection may typically bring up. These can be considered carefully beforehand, e.g. which internal documents need to be kept at hand for a certain question - this will save some moments of panic during the inspection. US inspectors, in particular, like to use checklists, such as those in the Compliance Policy Guides or Compliance Policy Manual, to prepare themselves for the inspection. These sorts of checklists can also be used by the auditee as a useful preparatory aid.

However, when using checklists to prepare for an inspection, it must be taken into consideration, that:

  • Simply filling in these lists can at best provide an initial overview. However, it does not replace the intensive challenge of the individual Quality System in place.
  • Checklists can never be as comprehensive, exhaustive or specific enough to do justice to the situation at every (pharmaceutical, supplier, packaging, etc.) company with all the various product ranges, different equipment pools and organisational differences.
  • On the other hand, it will also include many questions that may not be applicable to the particular (pharmaceutical, supplier, packaging, etc.) company. However, it is still useful to be prepared for these questions so that you are not irritated during the actual inspection and can point out that a certain requirement only applies to pharmaceutical products, for example and not to active pharmaceutical ingredients, etc.
  • Specific national legal requirements may have to be considered in addition.

A list of questions can also be useful for the auditor when preparing for the inspection to ensure that all the relevant aspects are discussed. Nevertheless, an inspection is not only about asking the right questions, but also assessing the corresponding answers. A checklist cannot take on this task. The checklist alone is often unsatisfactory for documenting the findings during the inspection (e.g. marking yes or no). More meaningful descriptions are very important in order to classify the deficiency (figure 18.D-10).

The following is a catalogue of typical general questions which may be asked during an inspection. Chapter 18.I Supplier qualification contains a list of questions to be considered by manufacturers of active pharmaceutical ingredients when preparing for an inspection.

The questions are referenced to the corresponding GMP regulations. In cases of doubt, the relevant original text can be quickly found.

A table divided up as follows is recommended for documenting the answers during an inspection:

Question

yes
or fulfilled

partially fulfilled/

acceptable

partially fulfilled/not acceptable

no

Comment/examined document

1.

         

2.

         

etc.

         

The following regulations are used in the tables below as references:

  • CFR: Code of Federal Regulations (US GMP regulations) see chapter I.1
  • EU GMP Guideline: Guidelines to Good Manufacturing Practice of Medicinal Products for Human and Veterinary Use with a total of 18 appendices (labelled A 1-18), see chapter C EU GMP Guide.
  • IPEC: The IPEC Good Manufacturing Practices Guide for Bulk Pharmaceutical Excipients, The International Pharmaceutical Excipients Council (IPEC) (2001)
  • GMP Manual: Further information about this question in the GMP Manual in the chapter specified

    Figure 18.H-1 Typical questions which might be put during a GMP inspection  

    Typical audit questions

    CFR
    reference

    EU GMP
    Guideline

    IPEC

    GMP Manual
    chapter

    Opening discussion

    		     

    18.D.3.1

    1. Name and function of all persons present at the meeting

    -

    -

    		   

    2. Have there been any changes with regard to the company's ownership or corporate identity?

    601.12

    		     

    3. Have any additions or changes been made to the buildings or facilities which could affect the manufacture of the inspected product?

    601.12

    A15:43

    		   

    4. Is a current building floor plan available?

    601.12

    A15:12a

    		   

    Application file for marketing authorisation

    		       

    5. Do the actual manufacturing and testing procedures correspond to the marketing authorisation?

    		 

    1.2vii
    4.2

    		   

    Organisation chart, personnel

    		     

    2

    6. Have there been changes of personnel which could affect the product concerned?

    601.12

    		   

    2.C

    7. Were the authorities informed?

    		       

    8. Is a documented quality assurance system available?

    		 

    Chapter 1
    A18:2.11

    4.1
    4.2.2

    1

    9. Is a current organisation chart available?

    601.12

    2.2

    5.5.1

    		 

    10. Are there up-to-date detailed job descriptions for personnel who carry out GMP tasks?

    		 

    2

    A18:3.11

    5.5.1

    2.A

    11. Who is responsible for manufacturing?

    		 

    2.5

    		 

    2.C.1

    12. Does he/she have the necessary qualifications, knowledge and practical experience?

    211.25

    2.4c

    		 

    2.C.1

    13. Does he/she have sufficient skills/competences?

    		 

    2.2

    		 

    2.C.1

    14. Is there a quality control unit in place?

    211.22

    6.1

    		   

    15. Who is responsible for quality control?

    		 

    2.6

    6.1-6.2

    A18:2.13

    A18:2.22

    		 

    2.C.2

    16. Are intermediate and/or final products approved by authorised persons?

    211.22d

    A18:2.14 and 2.22

    		 

    14.J.1.1

    17. Do they have the necessary qualifications, knowledge and practical experience?

    211.25

    2.4c
    6.1

    		 

    14.J.1.1

    18. Do they have sufficient skills/competences?

    		 

    2.2
    6.1

    		 

    14.J.1.1

    19. Are the responsibilities and procedures of the Quality Control Unit laid down in writing?

    211.22

    1.2iii
    A18:2.13 and 2.22

    		 

    2.C.2

    20. Is there an adequate number of qualified personnel in manufacturing and packaging?

    211.25c

    1.3iiia
    1.4i
    2.8-2.12
    A18:3.1

    6.1

    6.2.1

    2.B.1

    21. Is there a written training plan for employees? Does it include GMP regulations?

    211.25 a

    1.3v
    2
    2.9
    4.26
    A18:3.12

    6.2.2

    2.D.3

    22. Are there written records maintained of employee training?

    211.25

    2.9
    A18:3.12

    6.2.2

    2.D.8

    23. Are the qualifications of consultants checked?

    211.34

    A18:3.30

    6.2.4

    18.C

    24. Is there a list of all consultants, their addresses, qualifications and the tasks they perform?

    211.34

    A18:3.31

    6.2.4

    		 

    25. Is there a procedure in place for informing all the responsible management personnel in the event of inspections by the authorities, severe GMP deficiencies, product failures and the associated actions (complaints, recalls)?

    211.180f

    A18:2.18

    5.5.2
    8.2.2

    		 

    Buildings and infrastructure

    		       

    26. Are all buildings and rooms of a suitable size, design and location to facilitate cleaning, maintenance and proper operations? Are they qualified?

    211.42
    211.58
    600.11

    1.3iiib
    Kap 3, A18:41

    6.3.1

    3.A
    3.G

    27. Are buildings/rooms kept in an adequately clean, hygienic and tidy condition?

    211.56a

    3

    6.3.1

    6.4.1

    11.D

    28. Are separate or defined areas of sufficient size available for
    · Incoming goods?

    211.42c1

    3.20
    A18:4.14

    		 

    11.M.2.3

    29. · Storage of raw materials?

    211.42c1

    3.18
    5.7
    A18:4.14

    		 

    11.M.2

    30. · Storage of packaging materials?

    211.42c1

    1.3iiif
    3.25

    		 

    13.A.4.3

    31. · Weighing?

    		 

    3.13

    		 

    11.G

    32. · Manufacture?

    211.42c5

    3.1 - 3.8
    A18:4.14

    		 

    3.A
    3.C

    33. · Packaging?

    211.42c6

    3.15

    		 

    3.A

    3.C

    34. · Quality control?

    211.42c9

    3.26 - 3.29
    A18:4.14 and 4.16

    6.3.1

    3.A

    35. · Storage of semi-finished or in-process materials?

    211.42c4

    1.3iiif
    5.36

    		 

    3.A

    36. · Storage of finished products?

    211.42c8

    5.58-5.60

    		 

    11.M.2

    37. · Storage of highly toxic medicinal products and narcotic substances?

    		 

    1.3iiif
    3.24

    		 

    11.M.2.6

    38. Are the rooms used exclusively for their intended purpose?

    		 

    3.5
    A18:4.43

    		   

    39. Is the material flow and the production process logical so as to minimise the risk of mixups or omission of manufacturing or testing steps?

    211.42b+c

    3.8
    3.38
    A18:4.13
    A18:5.26

    		 

    3.C
    11.J

    40. Are different tasks carried out in areas set up especially for that purpose and which are of an appropriate size and which have suitable equipment so as to prevent contamination and mix-up?

    211.42

    3.7 - 3.8
    3.14
    5.18-5.20
    A18:4.13

    		 

    11.J.1

    41. Are measures taken to avoid cross-contamination?

    211.42

    3

    3.6

    3.8

    3.14

    3.15

    5.9

    5.18-5.20

    A18:4.13

    7.5.1.4

    9.1

    11.J

    42. Is there adequate lighting and ventilation?

    211.44

    3.3

    3.12

    3.16

    A18:4.21 and 4.5

    6.4.3

    7.5.1.5

    3.A

    3.B.4

    3.F

    3.H

    43. Are there separate ventilation systems for highly potent active pharmaceutical ingredients?

    211.46

    3.6

    		 

    3.H

    44. Are the rooms fitted out so that the walls, ceilings and floors cannot emit particles into the room.

    211.

    42c10i

    1.3iiib

    3.9

    		 

    3.E

    45. Are the rooms easy to clean and, if necessary, to disinfect?

    211.42
    211.56

    3.9

    3.14

    		 

    3.B.5

    46. Is the access to GMP-areas restricted to authorised personnel?

    211.28c

    3.5

    5.16

    6.2.3

    3.A

    3.B

    47. Are the water systems adequate?

    211.48

    3.43

    A18:4.3

    6.4.4

    7.5.1.7

    5

    48. Are waste and sewage disposed of safely and hygienically?

    211.50

    211.56a

    3.11

    A18:4.24 and 4.6

    6.4.1

    6.4.4

    		 

    Sanitation

    49. Is there a written sanitation programme?

    211.56

    2.13

    3.2

    4.26

    A18:4.71

    6.4.1

    11.D

    50. Does it contain responsibilities as well as cleaning intervals, techniques, equipment and materials?

    211.56

    3.2

    A18:4.71

    6.4.1

    11.D

    51. Is the sanitation programme followed?

    211.56

    3.2

    6.4.1

    		 

    52. Do the personnel practise good sanitation and health habits?
    Is direct contact with products avoided?

    211.28b

    2.13

    2.17-18

    A18:3.2

    6.2.1

    11.B

    53. Is eating and smoking prohibited in the manufacturing rooms?

    211.28b

    2.17

    		 

    11.B.3

    54. Is clean hygienic and protective clothing worn that is suitable for the activity performed?

    211.28a

    2.13

    2.16

    A18:3.21

    6.2.3

    11.B.1

    55. Are members of staff who are suffering from an infectious illness or who have open wounds wounds excluded from direct contact with products, in-process material, containers or raw material?

    211.28d

    2.14

    A18:3.24

    6.2.3

    11.B.5

    56. Are there written procedures on how to prevent microbiological contamination of medicinal products? Are they complied with?

    211.113

    5.10

    		 

    11.B

    57. Are the rooms clean?

    211.56

    3.2

    A18:4.70

    6.4.1

    11.E

    58. Are the rooms free from rodents, birds, insects and other vermin?

    211.56c

    3.4

    A18:4.72

    6.4.2

    11.M.3.2

    59. Are there adequate clean toilet and washing facilities easily accessible from working areas?

    211.52

    2.19

    3.31

    A18:4.15

    6.4.5

    3.A

    60. Are there sufficient changing rooms?

    		 

    3.31

    		 

    3.C.2

    61. Is there a written environmental monitoring plan?

    211.

    42c10iv

    4.26

    		 

    11.E

    12.G

    62. · Are there records available?

    		 

    4.26

    		 

    11.E

    12.G

    63. · Are the measures carried out documented?

    		 

    4.26

    		 

    11.E

    12.G

    Apparatus and equipment

    64. Is the design, installation and location of all apparatus suitable for the intended purpose?

    211.63

    211.65

    3.34 - 3.39

    A9:2

    A18:5.10

    6.3.2

    2

    1

    6.D

    65. Is thorough cleaning facilitated?

    211.67a

    3.36

    A9:1

    A18:5.10

    6.3.2

    2

    11.J.2

    66. Are tanks, containers, pipes and pumps designed and installed in such a way that they can be easily cleaned and disinfected - without dead-legs and poorly accessible points?

    		 

    3.10

    A9:2

    A18:4.23

    		 

    4.I

    11.J.2

    8.B

    67. Are sufficient measures carried out during the manufacturing operation to prevent contamination of the medicinal products and their containers (including the packaging)?

    211.42b

    211.65b

    3.38

    7.5.1.1

    11.J

    68. Is the equipment constructed in a way, that surfaces which come into contact with products do not alter the quality of the products?

    211.65

    3.39

    A9:3

    A18:5.11 and 5.14

    7.5.1.1

    11.J.2

    69. Is defective equipment removed from the production or control area or clearly labelled as defective?

    211.

    160b4

    3.44

    		 

    11.J

    70. Are there up-to-date drawings available of the equipment and installations?

    		 

    A18:5.16

    		 

    4.F

    71. Are there written plans available for DQ, IQ, OQ, PQ and requalification?

    211.68

    4.26

    A15

    		 

    6.C

    6.E

    6.F

    6.G

    72. Are there specifications available and written protocols of regular calibration of measuring, weighing, recording and control equipment?

    211.68

    211.

    160b4

    211.194d

    3.41

    A15:19

    A18:5.3

    7.1

    7.6

    4.G

    73. Are there written procedures on how to clean and maintain the equipment?

    211.67

    3.36

    3.43

    A18:5.2

    7.5.1.2

    7.5.1.3

    8.B.2

    74. Are they complied with?

    211.67

    3.36

    7.5.1.3

    		 

    75. Are cleaning, maintenance and use of equipment documented, e.g. in equipment logs?

    211.182

    4.28
    A18:6.2

    		 

    11.H

    11.J

    76. Have the cleaning processes been validated?

    		 

    A15:36

    7.5.1.2

    8

    77. Are there written operating instructions for manufacturing and testing equipment?

    		 

    4.27

    		   

    78. Are logbooks kept (for major equipment)?

    211.67c

    211.182

    4.28
    4.29

    7.5.1.3

    4

    79. Are all the major apparatus and facilities identified and is this information included in batch records?

    211.105b

    4.17f

    4.18f

    4.2.4

    11.H.2

    15.C

    80. Are there records available on the cleaning and usage of the equipment?

    211.67c

    211.182

    4.28

    4.29

    A18:6.2

    7.5.1.2

    15.C

    81. Are there adequate controls for the computers and associated systems to ensure that changes to the (master) specifications can only be made by authorised personnel?

    211.68

    4.9

    A18:5.4

    		 

    9

    82. Is the data input and output checked for accuracy?

    211.68

    4.9

    A18:5.45

    		 

    9

    83. Are files backed up?

    211.68

    		   

    9

    84. Are fibre-releasing filters used for liquid filtration? If so, are additional non-fibre-releasing filters used as required?

    211.72

    		   

    12.C.4

    Control of raw materials and containers

    85. Is there a list available of all raw material suppliers?

    680.1

    A18:7.1

    		 

    11.H.1

    11.M.4

    86. How often is this list updated?

    680.1

    		     

    87. Have the suppliers been suitably qualified? How?

    		 

    1.2iv

    5.26

    A8:3

    A18:7.11 and 7.31

    7.4.1

    18.G

    18.K

    88. Are there supplier lists for all incoming raw materials, including those that are rejected?

    		 

    A18:7.11

    		   

    89. Are there records for all raw materials?

    211.180b

    4.19

    		 

    11.M.4

    90. · Do they contain details of their origin?

    		 

    5.26

    4.20d

    A18:7.13

    7.5.5.3

    11.M.4

    91. · Do they contain the date of receipt?

    		 

    4.20c

    		 

    11.M.4

    92. Are there written instructions which describe the
    · receipt,
    · identification,
    · storage,
    · handling,
    · sampling,
    · analysis and
    · release or rejection of raw materials and medicinal product containers?

    211.80

    211.82

    4.19 - 4.21

    5.2

    A18:7.10 and 7.33 and 7.4

    		 

    11.M.4

    93. Are these directions followed?

    211.80

    4.19 - 4.21

    		   

    94. Is each container identified with a unique code when it is received?

    211.80d

    4.21

    5.3

    A18:7.24

    		 

    11.H.1

    11.M.5

    95. Is there a status identification for each batch?

    211.80d

    5.29

    7.5.3.2

    11.H.1

    96. Are there adequate quarantine procedures in place?

    211.82b

    211.110d211.142

    4.21

    5.2

    5.5

    5.58

    A18:4.14

    A18:7.10 and 7.44 and 10.11

    7.5.3.2

    11.H.1

    11.M.2.5

    97. Are they complied with?

    211.82

    4.21

    		   

    98. Are all materials fully and satisfactorily assessed before they are approved or used?

    211.84a

    1.4

    A18:2.17 and 7.20

    7.4.3

    7.5.3.2

    14.J

    99. Are samples from each shipment of each batch taken, tested or examined correctly and approved for use by quality control?

    211.84a and e

    1.4ii

    4.22

    		 

    14.A

    100. Is at least one identity test carried out for each raw material? Are specific identity tests used?

    211.84d1

    5.30

    A18:7.30

    7.4.3

    14.A111.G

    101. Does the manufacturer rely on the suppliers' analysis reports? If yes, how does the manufacturer "validate" the suppliers' test results?

    211.84d2 and d3

    5.26 A18:7.30

    7.4.3

    18.G

    102. Are there written specifications which ensure that drug product containers and closures are suitable for their intended use?

    211.94

    211.130d

    		   

    13.A.3

    103. Are they complied with?

    211.94

    		     

    Sampling of starting materials and packaging materials

    104. Are the personnel who carry out the sampling sufficiently trained to do this correctly?

    		 

    1.4i

    4.22

    A8:1

    		 

    14.A.1.1

    105. Is each individual container sampled and identity tested or is there a validated process to ensure that not one single container can be incorrectly labelled?

    		 

    A8:2

    A8:3

    		 

    14.A.2

    106. Are there measures in place to prevent contamination/cross-contamination of the sampled material during sampling?

    211.84c2

    A18:7.34

    		 

    14.A.3

    107. Is the number of samples taken determined statistically and set out in a sampling plan?

    211.84b

    211.165c

    1.4ii

    A8:4

    A18:7.33

    		 

    14.A.2

    108. Is the number of individual samples defined, which are to be blended to form
    a composite sample ?

    		 

    A8:4

    		 

    14.A.2

    109. Are the packaging material manufacturers audited?

    		 

    A8:5

    		 

    18.K.3.7

    110. Are the sampling plans for packaging materials sufficiently detailed?

    		 

    4.22

    A8:5

    		 

    13.A.4

    Storage and distribution

    111. Are there written instructions for storage and quarantine procedures?

    211.82b

    211.142

    211.110d

    1.3iiif

    5.2

    5.58

    A18:7.10 and 7.4 and 10.1

    		 

    11.M

    112. Are they complied with?

    211.142

    5.2

    5.58

    		   

    113. Are the containers stored correctly in the warehouse (e.g. under controlled conditions)?

    211.82

    211.142b

    3.18 - 3.25

    5.7
    A18:7.4

    7.5.5.1

    11.M.3

    114. Are the containers in the warehouse correctly labelled?

    211.80d

    211.82

    5.29 A18:8.11

    7.5.3.3

    11.M.4

    11.M.5

    115. Are the containers free from any damage?

    211.82a

    5.27

    		   

    116. Are rejected materials clearly labelled and controlled using a suitable quarantine system?

    211.89

    211.42c2

    211.110d

    3.23

    A18:4.14 and 7.44 and 10.1

    		 

    11.M.1

    11.M.2

    117. Does the "FIFO" (first-in first-out) or "FEFO" (first-expired first-out) principle apply in the warehouse?

    211.86

    211.150a

    5.7

    A18:7.42

    		 

    11.M.1.3

    118. Are there written instructions and records regarding distribution?

    211.150

    5.2

    A18:10.2

    		 

    11.M.6

    119. Are they complied with?

    211.150

    5.2

    		   

    120. Are products transported in such a way that their quality is not affected? Are special transport or storage conditions indicated on the label?

    		 

    1.2viii

    1.3iiif

    A18:10.21 and 10.22

    7.5.5.3

    7.5.1.20

    11.M.6

    121. Does the manufacturer make sure that the transport company knows and complies with the transport and storage conditions?

    		 

    A18:10.23

    7.5.5.3

    11.M.6

    122. Do the dispatch specifications/documentation make provision for a recall if necessary?

    211.150

    4.25

    A18:10.24

    7.5.5.3

    11.M.6

    123. Are returns labelled as such and placed in quarantine until a decision is made regarding their further use/destruction?

    211.204

    5.65

    A18:14.5
    and 17.8

    7.5.5.4

    11.M

    124. Are records kept on returns and their further disposition?

    211.204

    5.65

    A18:14.52 and 17.8

    7.5.5.4

    11.L.1

    125. Are there written instructions on how to deal with returns?

    211.204

    4.26

    5.65

    7.5.5.4

    		 

    126. Are they complied with?

    211.204

    4.26

    		   

    Manufacture and process controls

    127. Are there written instructions for production and process controls which ensure that an acceptable product is manufactured?

    211.100

    211.186

    211.188

    5.2

    A18:8.30

    7.1

    11.I

    128. Are manufacturing operations and controls carried out under the management and supervision of responsible specialists?

    211.25

    2.5

    A18:2.2 and 2.3

    		   

    129. Are there instructions regarding the validation of production processes?

    211.113b

    4.26

    5.21-5.24

    5.37

    A15

    9.2

    7

    130. Are weighing, measuring and sub-dividing operations adequately supervised? Is the addition of raw materials to the product verified by a second person?

    211.101

    A18:8.12

    		 

    11.G

    131. Is all equipment inspected for cleanliness immediately before use?

    211.67b6

    5.35

    A18.5.21

    		 

    11.J.2

    11.H.2

    132. Are all the vessels, containers, machines, major equipment and pipes clearly and visibly identified?

    211.101b

    211.105

    3.42

    5.12

    5.13

    A18:5.26 and 5.13 and 4.23 and 8.11 and 8.16

    		 

    11.J.3

    133. Is the content and the manufacturing step always indicated on the equipment/containers?

    211.105a

    5.12

    A18:8.16

    		 

    11.H.2

    134. Are actual yields and percentages of the theoretical yield determined at the end of each manufacturing step (if meaningful)?

    211.103

    211.

    188b7

    4.14d

    4.17h

    5.8

    5.39

    A18:8.14

    4.2.4

    15.C

    135. Are these calculations verified by a second person?

    211.103

    6.16

    		 

    15.C

    136. Are there written instructions for in-process controls (IPC)? Are they complied with?

    211.110

    4.14d A18:8.3

    7.5.1.13

    11.I

    137. Are IPC techniques authorised by quality control?

    		 

    6.18 A18:8.32

    		 

    11.I

    138. Are there time limits established for completion of each manufacturing step?

    211.111

    A18:8.2

    		 

    15.C

    139. Are deviations from specifications documented, justified and authorised?

    211.110b

    211.111

    4.17i

    5.15

    5.39

    5.56

    A18:2.16

    4.2.4

    9.2.2

    11.K

    140. Are intermediate products and bulk stored under suitable conditions?

    		 

    5.36

    A18:17.4

    		 

    11.J

    3.A

    141. Are there procedures for reworking products that do not comply with the specifications?

    211.115

    211.165f

    5.62 A18:14.2 and 14.3

    		 

    11.L

    142. Are only sub-batches or intermediate products which correspond to the specification blended to give a homogeneous batch?

    		 

    A18:8.4

    7.5.1.10

    		 

    143. Is there a "manufacturing history" (list of all the manufactured batches of the product concerned, including defective batches)?

    211.

    180e1

    		   

    15.F

    Packaging and label control

    		       

    144. Are there written instructions which describe receipt, identification, storage and handling of labels and packaging materials in detail?

    211.122a

    4.19

    5.40

    5.57 A18:9.10

    		 

    13.A

    145. Are records kept for each shipment of labeling or packaging material indicating the results of inspection?

    211.122c

    4.19

    A18:9.12

    		 

    13.A

    146. Are the labels for each different product stored separately and suitably identified?

    211.122d

    3.25

    5.41

    5.42

    		 

    13.A.4

    147. Is access to the label storage locations controlled?

    211.122d

    3.25

    5.41

    A18:9.30

    		 

    13.A.4

    148. Are out of date or obsolete labels and packaging materials destroyed?

    211.122e

    5.43

    A18:9.33

    		 

    13.A

    149. Are excess labels/packaging materials bearing batch/control numbers destroyed?

    211.125d

    4.18I

    5.57

    A18:9.32

    7.5.1.11

    13.A

    13.B.12

    150. Are there written instructions which describe labelling issuance in detail? Are they complied with?

    211.125f

    5.41

    A18:9.31

    7.5.1.11

    13.B.1

    151. Are discrepancies investigated and reported?

    211.125c

    211.192

    5.56 A18:9.31

    		 

    13.B.2

    152. Has it been shown that containers are suitable and that they provide sufficient protection against deterioration or contamination during storage and transport?

    211.94b

    A18:9.2

    7.5.5.2

    14.G.2

    153. Are containers and closures stored in such a way that contamination, damage and mix up/misidentification can be prevented?

    211.80b-d

    211.122d

    		 

    7.5.5.1

    13.A.4

    154. Are there written instructions to ensure that the correct labels and packaging materials are used?

    211.130

    4.16 A18:9.35 and 9.40

    7.5.1.11

    13.B.2

    155. Are packaging and labelling results documented in batch processing records or batch packaging records?

    211.130d

    4.18g

    A18:9.35

    4.2.4

    15.C.2

    156. Are packaging and labelling activities carried out in such a way that mix-ups are prevented, i.e. physically or spatially separated from other products?

    211.130a

    5.44

    A18:9.41

    7.5.1.11

    13.B

    157. Are there written procedures for the complete removal from previously used material, cleaning and inspection of packaging areas before the next packaging operation?

    211.130e

    211.

    188b6

    4.16f

    5.45

    4.2.4

    13.B.2

    158. Are tamper-evident closures or seals (seals for tank waggons or HGVs) used?

    211.132

    		 

    7.5.5.2

    		 

    159. Are packed and labelled products adequately? Are a representative number of packages sampled after completion of packaging operations and visually examined for correct labelling?

    211.134

    4.16h

    5.54

    A18:9.45

    		 

    14.A

    160. Are the results of these investigations entered in the batch records?

    211.134c

    5.55

    A18:9.45

    		 

    14.I

    15.C.4

    161. Do the products bear an expiration date which has been determined in stability studies?

    211.137

    211.166

    4.16e

    7.5.1.20

    14.G

    Laboratory controls

    162. Are there adequate written instructions that ensure that raw materials, containers, in-process materials, labels and products correspond with the actual standards (specifications) with regard to identity, strength, quality and purity?

    211.22d

    211.160

    211.165

    4.23

    6.2 A18:11.11

    		 

    15.C.4

    163. Are these instructions authorised by quality assurance?

    211.160a

    1.4ii

    A18:

    11.12

    		   

    164. Do all the specifications, sampling plans and analytical procedures have a scientific basis?

    211.160b

    1.4ii

    A18:11.12

    7.5.1.12

    14.A

    15.C.4

    165. Are there written instructions to ensure that the samples are representative and adequately labelled?

    211.84

    211.160

    1.4ii

    4.22

    6.11-6.13

    A8:4 A18:7.33 and 11.12

    		 

    14.A

    166. Are there written instructions for calibrating instruments, measuring and recording devices with exact specifications, schedules, limits for accuracy and precision and procedures in the event of deviations?

    211.
    160b4

    3.41

    4.26

    A18:12.82

    7.6

    14.E

    167. Are there complete calibration records?

    211.194d

    4.26

    		 

    14.E

    168. Have the precision, sensitivity, selectivity and reproducibility of the test methods been validated?

    211.165e

    211.

    194a2

    1.4iii

    6.15

    A15:22

    A18:12.8

    		 

    14.F

    169. Is there a written test programme designed to assess the stability characteristics of products?

    211.166

    6.2 A18:11.5

    7.5.1.19

    14.G

    170. Is a sufficient number of batches of each product tested to determine the stability?

    211.137

    211.166

    4.16e

    A18:11.5

    		 

    14.G

    171. Are the stability tests that are carried out fully documented and archived?

    211.194e

    A18:11.5

    7.5.1.19

    9.2.3

    14.G

    172. Are retention samples stored from each batch of each shipment of each active pharmaceutical ingredient/medicinal product?

    211.170

    1.4viii

    6.2

    6.14

    A18:11.7 and 19.81

    7.5.1.15

    14.A.3.3

    173. Are the retention samples stored in identical or comparable packaging to the commercial product?

    		 

    1.4viii

    6.14

    A18:11.72

    		 

    14.A.3.3

    174. Are there written procedures for the approval and rejection of materials and products?

    211.84a and e

    211.122b

    211.165

    1.2v

    1.4vii

    4.24

    A18:2.22

    7.5.1.14

    14.J

    175. Are approved starting materials/containers reinspected once they are expired or following exposure to harmful conditions (heat, moisture, etc.)?

    211.87

    211.

    160b1

    		     

    176. Is there a written procedure for handling results?

    211.160a

    A18:11.15

    4.2.4

    7.5.1.17

    14.H

    177. Are all deviations from specifications documented and investigated?

    211.100b

    211.160a

    1.4vi

    5.15

    A18:2.16

    9.2.2

    14.H

    178. Are changes in methods documented and compared to the established methods?

    211.194b

    		   

    14.F

    179. Are reagents and standards manufactured and labelled in accordance with written procedures?

    		 

    6.19-21

    A18:11.16

    7.5.1.16

    14.B

    14.C

    180. Is the handling of reference standards (source and manufacture, storage, analysis, use) documented?

    211.194c

    A18:11.17-11.19

    7.5.1.16

    14.C

    Rejection and salvaging

    A18:14

    		   

    181. Are materials that do not correspond to the specifications placed in quarantine?
    Is the further disposition (e.g. reprocessing, disposal) of such materials documented?

    211.42c2

    211.89

    211.110d

    211.122b

    211.165f

    211.184e

    5.61

    A18:7.44 and 14.1

    8.3

    11.M.2.5

    182. Is a careful investigation of the cause of failure carried out before reprocessing or reworking?

    211.115

    A18:14.30

    8.3

    11.L

    183. Before reprocessing or reworking, is there an investigation into whether the quality of the materials would be negatively affected by the reprocessing/reworking (e.g. creation of by-products, stability)?

    211.165f

    5.62

    5.64

    A18:14.22

    8.3.1

    11.L

    184. Are there written procedures describing the cleaning of reusable containers (for active pharmaceutical ingredients or excipients)?

    		 

    A18:9.22

    7.5.5.2

    11.J.2

    Documentation (instructions, records and reports)

    A18:6

    		   

    185. Are there current operating procedures which are accessible to all staff?

    		 

    1.3iv

    		 

    15.D

    186. Are the operating procedures regularly reviewed, updated, authorised by responsible persons and taught to staff?

    		 

    1.3iiie and v

    4.3

    4.5

    		 

    15.D

    187. Are all quality-relevant activities documented at the time they are carried out?

    211.100b

    211.160a

    211.182

    1.3vi

    4.8

    A18:2.15 and 6.14

    4.2.4

    15.A

    188. Are cleaning, maintenance and usage records available for all major equipment?

    211.182

    4.26

    A18:6.2

    		   

    189. Are there complete records (supplier, test results, usage) for starting materials, medicinal product container, closures and labels?

    211.184

    4.11

    4.19

    5.2

    A18:6.3

    7.5.3.1

    15.C

    190. Do they also include receipt of each delivery, test or examination record, inventory records of each material and and label checks?

    211.

    184 a-d

    4.19

    5.2

    A18:6.3

    		 

    15.C

    191. Are the master manufacturing instructions and control procedures available and complete?

    211.186

    4.14

    4.15

    A18:6.4

    		 

    15.C

    192. Are these checked, dated and signed by a second independent person?

    211.186

    A18:6.40

    		 

    15.C

    193. Are the manufacturing instructions and control procedures (batch documentation) available and complete? Is the corresponding master record reproduced precisely?

    211.188

    4.17

    A18:6.5

    4.2.4

    15.C

    194. Are all the manufacturing and control documents used authorised by persons entitled to do so?

    211.186

    4.3

    A18:2.21

    		 

    15.C

    195. Are all production and control records reviewed by a quality assurance function before the product is released?

    211.192

    1.2vii

    6.3

    A18:2.21 and 6.71

    7.5.1.14

    14.J

    196. Is the collection of critical data checked by a second person?

    211.192

    211.

    194a8

    4.9

    A18:6.52

    and 6.60

    		 

    15.C

    14.J

    197. Is there a written procedure for investigating and documenting deviations?

    211.100b

    211.192

    211.160a

    1.3vi

    A18:2.16

    and 6.53

    9.2.2

    14.H

    198. Are the test documents (sampling records, laboratory records, physical and chemical determinations, all raw data, calculations and results) available and complete?

    211.194

    211.160

    4.23

    6.17

    A18:6.6

    7.5.1.16

    14.I

    199. Are the distribution records available and complete?

    211.196

    1.3vii

    4.25

    		 

    11.M.6

    200. Are the production, control and distribution records which are specifically related to a product batch kept for at least one year after the expiration date so that they are readily available to an authorised inspector?

    211.180

    4.8

    4.9

    A18:6.13

    4.2.4

    15.B

    201. Is an annual product review (APR) carried out?

    211.180e

    A18:2.5

    8.2.4

    15.F

    202. Is there sufficient security with regard to computer system access, data modifications and record manipulation?

    		 

    4.9

    A18:5.43

    4.2.3

    7.1

    15.B.1

    203. Are adequate back-up measures in place to ensure that the data is available?

    		 

    4.9

    A18:5.48

    7.1

    15.B

    Contract manufacturing and analysis

    204. Are there written contracts or formal agreements which set out the GMP responsibilities of both parties and the quality measures in detail?

    		 

    7.1

    7.2

    7.10-7.15 A18:16.12

    7.2.2

    7.4.2

    5

    8

    205. Are audits carried out at contract acceptors premises?

    		 

    7.14 A18:16.11 and 16.13

    		 

    6

    206. Does the contract giver keep manufacturing, testing and distribution reports, as well as retention samples, or are they available to him?

    		 

    7.13

    		 

    17.A

    207. Is traceability guaranteed at the contract acceptor?

    		 

    7.8

    A18:16.10

    7.5.5.3

    17.A

    208. Are changes in the process, equipment, test methods, specifications or other contractual requirements only made after information and approval by the contract giver?

    		 

    7.2

    A18:16.16 and 13.17

    7.2.3

    7.5.1.21

    17.A

    209. Does quality control take on the responsibility for approving/rejecting products that are manufactured, processed, packaged or stored at contract manufacturers?

    211.22

    7.3

    5.5.1

    17.A

    210. Is it guaranteed that the contract giver will be informed if the contract acceptor subcontracts parts of the work?

    		 

    7.8

    A18:16.14

    		 

    17.A

    Complaints and recalls

    		     

    211. Are there written procedures in place for recalls?

    		 

    1.3ix

    4.26

    8.9

    7.13

    A18:2.18 and 15.13

    And 17.7

    		   

    212. How often are the recall procedures updated?

    		 

    8.9

    		   

    213. Are the recall procedures checked for their effectiveness?

    		 

    8.9

    8.15

    		   

    214. Is there a complaints list?

    211.198

    8.6 A18:15.10 and 17.7

    7.2.3

    		 

    215. Is there a written procedure for handling complaints?

    211.198

    1.3x

    4.26

    6.2

    8.2

    A18:2.18 and 15.10 and 17.7

    5.5.1

    		 

    216. Are there measures in place to prevent errors from occurring again?

    		 

    1.3x

    8.4

    A18:2.41 and 2.51
    and 15.12 and 17.7

    		   

    Self-inspection

    217. Is the QA system regularly evaluated with regard to effectiveness and suitability?

    		 

    1.2ix

    5.6.1

    9.2

    1

    218. Are there written plans for carrying out self-inspections?

    		 

    9.1

    A18:2.4

    8.2.2

    9.2

    18.E

    219. Are they complied with?

    		 

    9.1

    8.2.2

    18.E

    220. Are the audit findings and proposed corrective actions documented and brought to the attention of responsible management?

    		 

    9.3

    8.2.2

    18.E

    221. Are corrective actions completed in a timely and effective manner?

    		 

    9.3

    A18:2.41

    8.2.2

    18.E.4

    Liquids, creams and ointments

    222. Does the processing and transport take place in closed systems?

    		 

    A9:1

    		   

    223. Are open products and open cleaned vessels ventilated with filtered air?

    		 

    A9:1

    		   

    224. Is glassware avoided?

    		 

    A9:3

    		   

    225. Is the chemical and microbiological quality of the water specified and is it monitored?

    		 

    A9:4

    		 

    5.A

    226. Is there careful maintenance of the water systems?

    		 

    A9:4

    		 

    5.E.1

    227. Is there a validated flushing procedure of the water system after every chemical disinfection?

    		 

    A9:4

    		 

    5.B.3

    228. Is the quality of substances that are received in tank waggons checked before they are transferred to bulk storage tanks?

    		 

    A9:5

    		   

    229. When materials are transferred via pipelines, can it be guaranteed that they are delivered to their correct destination?

    		 

    A9:6

    		   

    230. Are materials likely to shed fibres (wood, cardboard), materials (wood, cardboard) kept away from products and cleaned containers?

    		 

    A9:7

    		   

    231. Is it guaranteed , that homogeneity of mixtures, suspensions, etc. is maintained during filling operations? Are mixing and filling procedures validated?

    		 

    A9:8

    		 

    7

    232. Is the maximum storage duration/storage conditions specified if filling is not to take place immediately?

    		 

    A9:9

    		   

    Qualification and validation

    7.5.2

    		 

    233. Are major changes to facilities, equipment and processes validated?

    		 

    1.3ii

    5.23

    A15:1 and 20

    		 

    7

    234. Are risk assessments carried out to determine the scope and depth of the validation?

    		 

    A15:2

    		 

    7.G

    235. Is there a validation master plan (VMP) or comparable document?

    		 

    A15:2 A18:12.10

    		 

    7.F

    236. Is the VMP a short, precise and clear summary document?

    		 

    A15:3

    		 

    7.F

    237. Does the VMP contain information about validation organisation, planning and scheduling and change control?

    		 

    A15:4

    		 

    7.F

    238. Are there written instructions for qualification or validation specifying critical steps and acceptance criteria?

    		 

    A15:6

    		 

    6.A

    6.C

    239. Are there qualification or validation reports which
    · cross-reference the qualification and/or validation protocol
    · summarise the results
    · comment on deviations
    · draw conclusions
    · make recommendations for follow-up actions if necessary?

    		 

    A15:7 A18:12.2

    		 

    6.C.3

    7.H

    240. Are changes to the protocol documented and justified?

    		 

    A15:7 A18:12.23

    		 

    6.C.2

    7.H

    241. Is a successful qualification followed by a formal written approval?

    		 

    A15:8 and 15

    		 

    6.C.4

    242. Is there a documented design qualification?

    		 

    A15:9 and 10 A18:12.3

    		 

    6.D

    243. Is an IQ implemented for new and modified facilities/equipment?

    		 

    A15:11 A18:12.3

    		 

    6.E

    244. Does the IQ include at least the following:
    · Installation of equipment, pipes, supply lines and instruments
    · Verification of current drawings and specifications
    · Compilation of operation, work, maintenance and calibration instructions
    · Verification of the construction materials?

    		 

    A15:12 A18:12.3

    		 

    6.E

    4.E

    245. Is an operational qualification (OQ) carried out after the IQ?

    		 

    A15:13 A18:12.3

    		 

    6.F

    246. Do the OQ tests include the upper and lower operating limits?

    		 

    A15:14 A18:12.3

    		 

    6.F

    247. Following a successful OQ
    · Are calibration, operation and cleaning processes and preventative maintenance requirements established
    · Are operating personnel trained
    · Is the facility/equipment approved?

    		 

    A15:15

    		 

    6.F

    248. Is a performance qualification (PQ) carried out following a successful IQ and OQ or is the PQ carried out together with the OQ?

    		 

    A15:16 and 18 A18:12.3

    		 

    6.F

    249. Does the PQ include at least
    · Tests with production materials or qualified substitutes/simulated products?
    · Tests that include the upper and lower operating limits?

    		 

    A15:17

    		 

    6.F

    250. Is data available for facilities that are already in use which
    · verifies operational parameters and
    · limits for critical variables?
    · Are there written instructions for calibration, cleaning, maintenance and operation in place?
    · Are the operators adequately trained?

    		 

    A15:19

    		 

    H

    251. Are all processes validated prospectively - or concurrently in exceptional cases - and are long-established processes validated retrospectively?

    		 

    A15:21 and 28 A18:12.4

    7.2.2

    7.5.2

    7.B

    252. Have critical process steps/process parameters been identified and validated?

    		 

    A15:24b

    A18:12.44(1) and 12.51

    9.2

    9.2.1

    9.2.4

    7.G

    253. Are all the facilities/equipment qualified, the test methods validated and the staff trained before the process validation is performed?

    		 

    A15:22 A18:12.3

    		 

    7.E

    254. Does the validation protocol include at least
    · A short process description
    · The critical process parameters
    · All equipment to be used, including calibration status
    · Approval specifications for the finished product
    · Methods of testing
    · IPCs including methods of testing
    · Sampling plan
    · Recording and evaluation techniques
    · Responsibilities
    · Schedule

    		 

    A15:24

    		 

    7

    255. Are at least three successive batches manufactured within the final established parameters for the process validation?

    		 

    A15:25 A18:12.50

    		 

    7.C.1

    256. Are the validation batches the same size as the batches intended for the market?

    		 

    A15:26

    		 

    7

    257. Are validation batches which are intended to be sold or supplied manufactured according to GMP and in conformity with the marketing authorisation?

    		 

    A15:27

    		 

    7

    258. In case of a concurrent validation, has the rationale been adequately justified, documented and authorised by a person who is entitled to do so?

    		 

    A15:29

    A18:12.43

    		 

    7.C.3

    259. In the case of a retrospective validation, was there a check for recent changes to the composition, operating process or equipment?

    		 

    A15:31 A18:12.44

    		 

    7.C.2

    260. Was a validation protocol drawn up for the retrospective validation?

    		 

    A15:32

    		 

    7.C.2

    7.F

    261. Were at least the following data reviewed for the retrospective validation:
    · Batch production records
    · Batch packaging records
    · Process control diagrams
    · Maintenance logbooks
    · Records of changes
    · Process capability investigations
    · Data on the finished product
    · Trend maps
    · Stability results?

    		 

    A15:33

    		 

    7.C.2

    262. Are the batches selected for the retrospective validation representative of all the batches manufactured during the period considered (including OOS)?

    		 

    A15:34

    A18:12.45

    		 

    7.C.2

    263. Were sufficient batches reviewed retrospectively to be able to prove the reliability of the process (ten to thirty successive batches)?

    		 

    A15:34, 35

    		 

    7.C.2

    264. Is the rationale for selecting limits in the cleaning validation logically based on the materials involved (product residue, cleaning agent residue, microbial contamination). Are the limits achievable and verifiable ?

    		 

    A15:36

    A18:5.26

    A18:12.72 and 12.74

    		 

    8.E

    265. Are the test methods for cleaning validation validated and proven to be sufficiently sensitive?

    		 

    A15:37 A18:12.74

    		 

    8.G

    266. Have the maximum intervals between use and cleaning and between cleaning and use been specified?

    		 

    A15:38

    A18:5.21

    		 

    8.A

    267. Have the cleaning intervals and cleaning methods been specified?

    		 

    A15:38

    		 

    8.B

    268. Have the cleaning processes for similar products and processes been considered according to the "worst-case" principle?

    		 

    A15:39 A18:12.71

    		 

    8.D

    269. Have the cleaning processes been successfully completed three times in succession in order to prove that the method is validated?

    		 

    A15:40

    		 

    8.C

    270. For toxic or hazardous substances, are simulations carried out with substances with similar physicochemical properties?

    		 

    A15:42

    		   

    Change control

    271. Is there a written procedure which regulates the procedure in the event of intended changes to
    · Starting materials
    · Product components
    · Equipment
    · Process environment
    · Facilities
    · Production techniques
    · Test methods?

    		 

    A15:43 A18:7.14 and 13.10

    7.5.1.21

    7

    272. Do the change control procedures ensure that the desired product quality is achieved? Is sufficient data generated to prove this?

    		 

    A15:43 A18:13.13

    7.5.1.21

    7

    273. Are all changes formally requested, documented and authorised? Are the effects assessed (risk analysis) and the need for requalification and/or revalidation evaluated?

    211.100a

    A15:44 A18:13.13

    5.5.1

    7.5.1.21

    7

    274. Are all facilities, equipment, processes and cleaning processes assessed regularly in writing to evaluate the need for requalification and/or revalidation?

    		 

    5.24

    A15:23 and 45

    A18:2.5

    A18:12.6

    8.2.3

    7.D

    8.I

    6.G.2

    275. Are customers informed in case of changes?

    		 

    A18:

    13.17

    7.5.1.21

    17.A

    Manufacture of sterile medicinal products

    7.5.1.8

    		 

    276. Are there entrances to clean areas for personnel that are not via air locks?

    		 

    A1:1

    		 

    12.A-B

    277. Are there entrances to clean areas for materials or apparatus that are not via air locks?

    		 

    A1:1

    		 

    12.A-B

    278. Are the clean areas ventilated only through adequately effective filters?

    		 

    A1:1

    		 

    3.H.3

    279. Do operations with open products/open primary packaging materials take place on separate rooms from operations with closed final containers?

    		 

    A1:2

    		 

    12.A.3

    12.C

    280. How are the clean areas classified?

    		 

    A1:3

    		 

    3.D

    281. Are the specified clean area classifications complied with? „At rest"/in operation state?

    		 

    A1:3

    		 

    12.A

    12.G

    282. Is the "at rest" state achieved approximately 20 minutes after work has ended?

    		 

    A1:3

    		 

    12.A

    283. Is the particulate cleanliness in the room monitored during operation?

    		 

    A1:4

    		 

    12.A

    284. Is work in clean areas carried out by a minimum number of people?

    		 

    A1:13

    		 

    12.A

    285. Do all those who work in clean areas receive regular training in hygiene, microbiology and appropriate handling of sterile products? Including
    · Cleaning staff?
    · Maintenance staff?

    211.25

    A1:14

    		 

    12

    286. Are external parties carefully instructed and supervised?

    		 

    A1:14

    		 

    12

    287. Can it be guaranteed that persons who work with animal tissues or microbiological cultures only have access to clean areas in accordance with rigorous and clearly defined entry procedures?

    		 

    A1:15

    		   

    288. Are periodic health checks carried out? Are there measures in place if individual persons present an unacceptable microbiological risk?

    211.28d

    A1:16

    		 

    2.B.2

    11.B.5

    289. Are there written procedures for washing and changing clothes to keep contamination of clean clothes to a minimum?

    		 

    A1:17

    		 

    12.B

    290. Are wrist-watches, make-up and jewellery worn in clean areas?

    		 

    A1:18

    		 

    12.B

    291. Is the quality of the working clothing suitable for the cleanliness class?

    		 

    A1:19

    		 

    11.B.1

    292. Is the clothing worn in such a way that the product is protected from contamination?

    		 

    A1:19

    		 

    11.B

    293. Are hair and beards covered?

    		 

    A1:19

    		 

    11.B

    294. Is outdoor clothing brought into air locks which lead to class B or C?

    		 

    A1:20

    		 

    12.B

    295. Are face masks and gloves changed for at least each working session?

    		 

    A1:20

    		 

    12.B

    296. Is clean room clothing washed, cleaned and handled according to written instructions so that no additional contamination occurs and and fibres are not damaged (which may increase the risk of shedding particles)?

    		 

    A1:21

    		 

    11.B.1

    Aseptic processes

    7.5.1.8

    		 

    297. Has aseptic filling been correctly validated (at least 3 separate media fills, at least twice a year for each shift and each fill line, at least 14 days incubation period)?

    		     

    12.A.2
    E.5

    298. Are the results of microbiological monitoring considered when reviewing batch documentation for finished product release?

    		 

    A1:5

    		 

    12.G

    299. Is there additional microbiological monitoring following critical operations or following validation, cleaning or disinfection work?

    		 

    A1:5

    		 

    12.G

    300. Are there appropriate alert and action limits defined for particle and microbiological monitoring?

    		 

    A1:6

    		 

    12.G

    301. Are there written procedures for how to proceed if limits are exceeded and for corrective actions?

    		 

    A1:6

    		 

    12.G

    302. Are they complied with?

    		 

    A1:6

    		 

    12.G

    303. Are sterile starting materials handled in class A with grade B background?

    		 

    A1:12

    		 

    12.E

    304. Is the preparation of solutions which are to be sterile filtered during the process done in at least a grade C environment ?

    		 

    A1:12

    		 

    12.C.4

    305. Are partially closed containers handled either in grade A environment with grade B background or in sealed transfer trays in grade B environment?

    		 

    A1:12

    		 

    12.E

    306. Are ointments, creams, suspensions and emulsions prepared and filled in grade A environment with a grade B background?

    		 

    A1:12

    		   

    Isolator technology

    307. How is the air quality in the isolator and in the environment specified?

    		 

    A1:7

    		 

    2

    308. Is the air quality being monitored and the specifications being met?

    		 

    A1:7

    		   

    309. Has the isolator (air quality, integrity of the isolator) and all the critical operations (disinfection, transfer operations) been qualified and/or validated before use?

    		 

    A1:8

    		   

    310. Are leak tests carried out on the isolator and the glove/sleeve system? Are they carried out frequently enough?

    		 

    A1:9

    		   

    Blow-fill-seal technology

    311. How is the air quality at the facility and in the environment specified?

    		 

    A1:10

    		   

    312. Is the air quality being monitored and the specifications being met?

    		 

    A1:10

    		   

    313. What protective clothing is worn?

    		 

    A1:10

    		   

    314. Was the facility sufficiently qualified before use and were critical operations such as cleaning, sterilisation and aseptic assembly adequately validated before filling was started?

    		 

    A1:10

    		   

    Terminally sterilised products

    315. Is there an increased contamination risk during preparation?
    · Is microbial growth actively supported by the product?
    · Is there a long holding time before sterilisation?
    · Is preparation in closed vessels not possible?

    		 

    A1:11

    		 

    12.C

    316. In this case, is preparation done in at least a grade C environment?

    		 

    A1:11

    		 

    12.E

    317. Does filling take place in at least a grade C environment?

    		 

    A1:11

    		 

    12.E

    318. Is there an increased contamination risk during filling?
    · Due to a slow filling process?
    · Due to wide-necked containers?

    		 

    A1:11

    		   

    319. In this case, does filling take place in zone A with an environment of at least grade C?

    		 

    A1:11

    		 

    12.C

    320. Are ointments, creams, suspensions and emulsions prepared and filled in at least grade C environment before sterilisation?

    		 

    A1:11

    		 

    3.B.5

    3.E

    321. Are the surfaces in the clean rooms smooth, impervious and free from cracks?

    		 

    A1:22

    		 

    3.B.5

    3.E

    322. Are inaccessible niches, corners, ledges and sliding doors on which particles could collect avoided? Are shelves, cabinets and equipment kept to a minimum and designed in such a way that they can be easily cleaned?

    		 

    A1:23

    		 

    3.E.4

    323. Are there false ceilings? Are they sealed?

    		 

    A1:24

    		 

    3.B.5

    3.E

    324. Are doors, pipes and lines arranged so that there are no hard to clean niches, unsealed openings or surfaces?

    		 

    A1:23, 25

    		 

    12.A

    325. Are there drains or sinks in grade A/B areas which are used for aseptic processing?

    		 

    A1:26

    		 

    3.E.3

    326. Are drains/sinks in other cleanliness classes fitted with air breaks and are floor drains fitted with traps or water seals to prevent backflow?

    		 

    A1:26

    		 

    12.B

    327. Are the changing rooms designed as air locks? Are the individual changing procedures physically separated from each other so that particulate contamination of the protective clothing is minimised?

    		 

    A1:27

    		 

    12.B

    328. Are the changing rooms effectively ventilated with filtered air?

    		 

    A1:27

    		 

    12.B

    329. Does the last zone in the changing room have the same grade (in the at-rest state) as the area into which it leads??

    		 

    A1:27

    		 

    12.B

    330. Are hand wash basins avoided in the last part of the changing rooms?

    		 

    A1:27

    		 

    12.B

    331. Are locks or audible or visual warning systems employed to prevent simultaneous opening of more than one air lock door?

    		 

    A1:28

    		 

    3.H.5.1

    332. Is there a positive pressure of approximately 10 - 15 Pascal between a neighbouring area with a lower cleanliness grade and is it maintained (opening a door)?

    		 

    A1:29

    		 

    3.H

    333. How is the airflow pattern resolved when pathogenic, radioactive or live viral or bacterial materials are being processed? How are the facilities decontaminated and the exhaust treated in these cases?

    		 

    A1:29

    		 

    3.H

    334. Has it been proven that the selected airflow pattern does not present any contamination risk, e.g. that no particles emitted from persons or machines are brought into higher risk zones?

    		 

    A1:30

    		 

    3.H

    335. Is there a warning system in place indicating malfunctions in the air supply?

    		 

    A1:31

    		 

    3.H.5.2

    336. Are differences in pressure between areas in which this is important regularly recorded and documented?

    		 

    A1:31

    		 

    12.E

    337. Are there conveyor belts between a grade A and operating areas with lower cleanliness classes? Are these conveyor belts continually sterilised?

    		 

    A1:32

    		 

    12

    338. Are equipment, fittings and operating elements arranged so that operation, maintenance and repair work can be conducted from the outside of the clean areas if necessary?

    		 

    A1:33

    		   

    339. Are clean rooms cleaned, disinfected and, if necessary, sterilised following maintenance work before processing recommences?

    		 

    A1:34

    		 

    5

    340. Are water purification and distribution facilities arranged so that a reliable water quality can be produced? Is the facility only operated up to its intended capacity?

    		 

    A1:35

    		 

    5.C

    341. Is water for injection treated, stored and distributed in such a way that microbial growth is prevented?

    		 

    A1:35

    		 

    5.E.1

    12.F.33.H.7

    342. Is all equipment maintained and qualified according to plan and is their return to use authorised?
    · Sterilisers?
    · Air treatment systems?
    · Air vent and gas filters?
    · Water treatment systems?
    · Water storage and distribution systems?

    		 

    A1:36

    		 

    11.D

    343. Is there a written sanitation programme for plant hygiene?

    		 

    A1:37

    4.9.4

    11.D

    344. Are disinfectants used?

    		 

    A1:37

    		 

    11.E

    12.G

    345. Are microbiological controls carried out?

    		 

    A1:37

    4.9.4

    11.E

    346. Are disinfectants and detergents monitored for microbiological contamination?

    		 

    A1:38

    		 

    11.C

    11.D

    347. Are unsterilised dilutions of disinfectants kept only in previously cleaned containers and for a specified time period?

    		 

    A1:38

    		 

    11.C

    11.D

    348. Are disinfectants and detergents sterilised for use in zones A and B?

    		 

    A1:38

    		   

    349. Is fumigation performed to reduce microbial contamination of inaccessible places?

    		 

    A1:39

    		 

    11.J

    350. Are precautions taken at all processing steps to keep contamination to a minimum?

    		 

    A1:40

    4.9.4

    		 

    351. Are preparations with microbiological origins (apart from vaccines of dead organisms or inactivated bacterial extracts) handled separately from other medicinal products?

    		 

    A1:41

    		 

    12.A.2

    12.E

    352. Are aseptic procedures validated? Does this validation include a media fill?

    		 

    A1:42

    		 

    12.E.5

    353. Does this process simulation include the routine manufacturing procedure as well as all the critical manufacturing steps?

    		 

    A1:42

    		 

    12.E.5

    354. Does the process simulation take worst case situations into consideration?

    		 

    A1:42

    		 

    12.E.5

    355. Are three successive successful simulations carried out per shift for the initial validation?

    		 

    A1:42

    		 

    12.E.5

    356. Are the process simulations repeated at defined intervals and after every significant change to ventilation systems, equipment, process or number of shifts?

    		 

    A1:42

    		 

    12.E.5

    357. What is the contamination rate? Has the manufacturer specified alert and action limits?

    		 

    A1:42

    		 

    12.E.5

    358. Is every contamination investigated?

    		 

    A1:42

    		 

    12.E.5

    359. Is it ensured that the validations do not compromise the manufacturing procedures?

    		 

    A1:43

    		 

    12.G

    360. Are the water sources, water treatment systems and treated water regularly monitored for impurities and endotoxins and are these results archived?

    		 

    A1:44

    		 

    11.B

    361. Do personnel carrying out aseptic work move in a controlled and methodical manner to avoid excessive shedding of particles and organisms?

    		 

    A1:45

    		 

    14.K

    362. Are starting materials tested for their microbiological quality?

    		 

    A1:46

    		   

    363. Is the use of materials and containers liable to generate fibres avoided in clean areas?

    		 

    A1:47

    		 

    12.I

    364. Are there measures in place to keep particle contamination of the final product to a minimum?

    		 

    A1:48

    4.9.4

    12

    365. Are containers and equipment handled in such a way that they are not recontaminated after final cleaning?

    		 

    A1:49

    4.9.4

    12

    366. Is the period between washing, drying, sterilising and use of material restricted depending on the storage conditions?

    		 

    A1:50

    		 

    12.C

    367. Is the period between manufacturing solutions and sterilisation/sterile filtration kept short or restricted depending on the storage conditions?

    		 

    A1:51

    		 

    12.C

    368. Is the bioburden monitored before sterilisation? Is the absence of pyrogens tested?

    		 

    A1:52

    		 

    12.C.4

    369. Are all solutions filtered through a micro-organism-retaining filter immediately before filling?

    		 

    A1:52

    		 

    12.B.2

    370. Are containers and accessories brought in only via sterilisers in aseptic work areas?

    		 

    A1:53

    		   

    371. Are non-combustible gases filtered through micro-organism retentive filters?

    		 

    A1:53

    		   

    372. Is the efficacy of every new procedure validated and the validation verified at scheduled intervals based on performance history or, in case significant changes are made, to the process or equipment?

    		 

    A1:54

    		 

    7

    373. Are all sterilisation procedures validated?

    		 

    A1:55

    		   

    374. Does the selected sterilisation procedure correspond with the marketing and manufacturing authorisations?

    		 

    A1:55

    		 

    12.F.4

    12.K.4

    375. Before new sterilisation procedures are introduced, was it demonstrated that the desired sterilisation conditions are achieved in all parts of each type of load?

    		 

    A1:56

    		 

    12.F.3

    12.K.3

    376. Have physical measurements and biological indicators been used for qualification?

    		 

    A1:56

    		 

    12.F.3

    377. Are sterilisers requalified at least once a year and following changes to the equipment?

    		 

    A1:56

    		 

    12.F

    378. Is the sterilisation process designed to guarantee that the whole of the material is effectively sterilized?

    		 

    A1:57

    		 

    12.F

    379. Are loading patterns established and validated for all the different sterilisation procedures?

    		 

    A1:58

    		 

    12.F

    380. Is the quality of bioindicators checked using positive controls?

    		 

    A1:59

    		 

    12.F

    381. Are there strict precautions in place to prevent any contamination when using bioindicators?

    		 

    A1:59

    		 

    12.F

    382. Are sterilised and unsterilised products clearly distinguished from each other?

    		 

    A1:60

    		 

    12.F

    383. Is every basket/tray containing products or components clearly labelled with the product name, batch number and a note of any sterilisation that has taken place?

    		 

    A1:60

    		 

    12.F

    384. Are there records for every sterilisation run which are approved as part of the batch release procedure?

    		 

    A1:61

    		   

    Heat sterilisation

    385. Are the sterilisation processes validated?

    211.113

    		 

    4.9.4

    12.F

    12.K

    386. Is every heat sterilisation cycle recorded with sufficient accuracy and precision?

    		 

    A1:62

    		 

    12.F

    12.K

    387. Is the position of the temperature probes determined during the validation?

    		 

    A1:62

    		 

    12.F

    12.K

    388. Are chemical or biological indicators used in addition?

    		 

    A1:63

    		 

    12.F

    12.K

    389. Is the heat-up time sufficient for the necessary temperature to be achieved throughout the entire load? Has this time been determined for every type of sterilisation load?

    		 

    A1:64

    		   

    390. Are there precautionary measures in place to prevent contamination during the cooling phase, e.g. by cooling fluid or gas?

    		 

    A1:65

    		 

    12.F

    Sterilisation using moist heat

    		       

    391. Are pressure and temperature monitored?

    		 

    A1:66

    		 

    12.F

    392. Are the control instruments independent of the monitoring apparatus and recording charts? Are automatic control and monitoring systems validated?

    		 

    A1:66

    		 

    12.F

    393. Are leak tests performed frequently on chamber if the cycle also includes a vacuum phase?

    		 

    A1:66

    		 

    12.F

    394. Are the items to be sterilized (other than products in sealed containers) wrapped in a material which allows removal of air and penetration of steam but which prevents recontamination after sterilisation?

    		 

    A1:67

    		 

    12.F

    395. Is the steam used for sterilisation of a suitable quality?

    		 

    A1:68

    		   

    Sterilisation using dry heat

    396. Does air circulation and maintenance of a positive pressure within the chamber prevent the entry of non-steril air?

    		 

    A1:69

    		 

    12.K

    397. Is any air admitted passed through HEPA filters?

    		 

    A1:69

    		 

    12.K

    398. Are challenge tests with endotoxins carried out as part of the validation if the procedure is also used for pyrogen removal?

    		 

    A1:69

    		   

    Sterilisation by radiation

    399. Has it been confirmed experimentally that the product (including the packaging material) is not adversely affected by the irradiation?

    		 

    A1:70

    		   

    400. Is the radiation dose recorded during the sterilisation procedure by independent dosimeters which are in sufficient number and close enough together in the load?

    		 

    A1:71

    		   

    401. Are plastic dosimeters used within the time limit of their calibration?

    		 

    A1:71

    		   

    402. Are the dosimeters read a short time after the radiation exposure?

    		 

    A1:71

    		   

    403. Is the effect of changes to the load density validated?

    		 

    A1:73

    		   

    404. Is irradiated and non-irradiated material handled in such a way as to prevent mix-up?

    		 

    A1:74

    		   

    405. Are additional radiation-sensitive colour discs used for identification?

    		 

    A1:74

    		   

    406. Is the total radiation dose administered within a predetermined time span?

    		 

    A1:75

    		   

    Sterilisation with ethylene oxide

    407. Was it confirmed during the process validation that the product was not adversely affected by exposure to the gas and that the degassing conditions and time have been selected such that residues of gas and reaction products are reduced to a specified level?

    		 

    A1:76

    		   

    408. Are precautions taken to avoid the presence of organisms likely to be enclosed in materials, such as crystals or dried protein?

    		 

    A1:77

    		   

    409. Are the materials brought up to the necessary temperature and humidity before exposure to gas?

    		 

    A1:78

    		   

    410. Is every sterilisation cycle monitored with suitable biological indicators distributed throughout the load and are the results recorded in the batch documentation?

    		 

    A1:79

    		   

    411. Is data on duration, pressure, temperature, humidity, gas concentration and total amount of gas used documented for every sterilisation cycle and is this included in the batch documentation?

    		 

    A1:80

    		   

    412. Is the load stored in a controlled manner under ventilated conditions for a validated time following exposure to gas?

    		 

    A1:81

    		   

    Sterile filtration without final sterilisation

    413. Has it been demonstrated that the product cannot be sterilised in the final container or subjected to heat treatment?

    		 

    A1:82

    		 

    12.C

    12.E

    414. Is the last sterile filtration carried out as close as possible to filling?

    		 

    A1:83

    		 

    12.C

    12.E

    415. Is the fibre shedding from the filters shown to be minimal?

    		 

    A1:84

    		 

    12.C

    12.E

    416. Is the integrity of the filter verified immediately before and after each use using a
    · bubble point test
    · diffusive flow test or
    · pressure hold test?

    		 

    A1:85

    		 

    12.C

    12.E

    417. Is the required filtration time per volume and the necessary pressure differential determined in the validation?

    		 

    A1:85

    		 

    12.C

    12.E

    418. Are all significant deviations from this in routine manufacture documented, investigated and recorded in the batch record?

    		 

    A1:85

    		 

    12.C

    12.E

    419. Is the integrity of critical gas and air filters confirmed after use?

    		 

    A1:85

    		 

    12.C

    12.E

    420. Is the same filter used for a maximum of one working day or has longer use been validated?

    		 

    A1:86

    		 

    12.C

    12.E

    421. Has it been shown that the filter does not adversely affect the product either through absorption of ingredients or through the release of substances?

    		 

    A1:87

    		 

    12.C
    12.E

    Finishing of sterile products

    422. Are the containers closed in accordance with validated methods?

    		 

    A1:88

    		 

    12.E

    423. Are glass or plastic ampoules subjected to 100 % integrity testing?

    		 

    A1:88

    		 

    12.I

    424. Are containers that are vacuum sealed tested for maintenance of that vacuum after a predetermined time?

    		 

    A1:89

    		   

    425. Are the filled containers individually tested for extraneous contamination and defects?

    		 

    A1:90

    		 

    12.I

    426. Are the visual control conditions adequate (lighting, background, pauses, eye-sight tests) and is the test method validated?

    		 

    A1:90

    		 

    12.I

    427. Are the results for the visual control recorded?

    		 

    A1:90

    		 

    12.I

    Quality control

    428. Is the sterility test validated for the product concerned?

    		 

    A1:91

    		 

    12.H

    429. In the case of parametric release, is special attention paid to the validation and monitoring of the entire manufacturing process?

    		 

    A1:92

    		 

    12.H

    430. Are the samples for sterility testing representative, in particular for those parts of the batch with increased contamination risk (start/end, interruption, coolest part of the load)?

    		 

    A1:93

    		   

    Trade of active pharmaceutical ingredients and excipients, including repackaging/relabelling

    431. Is there a procedure in place that ensures that traders and customers have agreed upon specifications and other requirements?

    		   

    7.2.2

    		 

    432. Is traceability of each active pharmaceutical ingredient/intermediate back to the original manufacturer guaranteed?

    		 

    5.26

    4.20d

    A18:17.2

    7.5.5.3

    		 

    433. Are the following documents available at all times
    · Identity and address of the original manufacturer
    · Purchase Orders
    · Transport documentation
    · Receipt documents
    · Name/designation of the product
    · Batch numbers of the original manufacturer
    · All authentic certificates of analysis
    · Re-test or expiration date?

    		 

    A18:17.2

    		   

    434. Is all quality and/or regulatory information (e.g. name of the original manufacturer and original batch number) forwarded to the customers?

    		 

    A18:17.6

    		   

    435. Is there a documented and fully functional quality management system implemented?

    		 

    A18:17.3

    4.2.2

    		 

    436. Is repackaging, relabelling and storage conducted under thorough GMP controls to prevent mix-ups and contamination?

    		 

    A18:17:4

    		   

    437. Are stability tests carried out if the product is repacked into a different container type?

    		 

    A18:17.5

    		   

    438. Are all complaints and recalls documented and reviewed in cooperation with the original manufacturer and the customer?

    		 

    A18:17.7

    5.5.1

    7.2.3

    		 

    439. Does the dispatch documentation allow full traceability to each customer and vice-versa, e.g. in the event of a recall?

    		 

    A18:7.13

    7.5.5.3

    		 

    440. Are returns and their further use documented?

    		 

    A18:17.8

    7.5.5.4

    		 

    Summary

    This catalogue of questions may be used as a tool for self- inspections or during preparation of regulatory or customer audits. As for all generic check-lists it must be taken into consideration, that the questions listed may not necessarily include all of the appropriate questions for a specific audit, nor are all points necessarily relevant to every inspected product or production site. Specific national legal requirements may have to be considered in addition.