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Consultations

Revised: 31 December 2012

Summary of differences between the New Zealand Code of Good Manufacturing Practice for Manufacture and Distribution of Therapeutic Goods Part 1: Manufacture of Pharmaceutical Products and the PIC/s Guide to GMP PE 009-8

Medsafe has conducted an internal review of the New Zealand Code of Good Manufacturing Practice for Manufacture and Distribution of Therapeutic Goods Part 1: Manufacture of Pharmaceutical Products against the PIC/s Guide to GMP and this is provided for general reference.

An approximate assessment of difference as minor, significant or voluntary has been provided as an indicator only. Medsafe advises manufacturers to independently assess the impact of changes.

Note : The points listed relate to the New Zealand Code of GMP unless enclosed within brackets. Text enclosed within brackets relates to the PIC/s Guide to GMP.

Table 1: Chapters 1 to 9
Chapter Title Point Description of difference Assessment of Difference
1 Quality Management All Pharmaceutical substituted with Medicinal Minor
1.1 (Principle) Addition of Quality Risk Management to the basic concepts of fundamental importance to the production and control of medicines Minor
1.2 (1.1) Removed separate reference to Good Laboratory Practice Minor
1.4 vii
(1.3 vii)
Broadened reference from 'marketing authorisation' to 'relevant authorisations' Minor
(1.4) Product Quality Review section added Significant
(1.5 & 1.6) Quality Risk Management points added Significant
2 Personnel All His/her substituted with his Minor
3 Premises and Equipment n/a No significant differences (pharmaceutical substituted with medicinal) Minor
4 Documentation n/a No significant differences (pharmaceutical substituted with medicinal) Minor
5 Production n/a No significant differences (pharmaceutical substituted with medicinal) Minor
6 Quality Control (6.23 - 6.33) Addition of section 'Ongoing Stability Programme' Significant
7 Contract Manufacture and Analysis n/a No differences None
8 Complaints and Product Recall 8.1 His/her substituted with his Minor
(8.7) Addition of clause regarding counterfeiting Minor
8.7 (8.8) Addition of counterfeiting as a potential reason for a complaint Minor
8.8 Addition of detection of counterfeiting to list of actions requiring notification of competent authorities. Minor
8.16 'from time to time' substituted with 'regularly' Minor
9 Self-Inspection n/a No differences None
Glossary This appears at the beginning of the NZ code and end of the PIC/s code - definitions for 'alert limit' and 'media fill' added Minor
Table 2: Annex 1: Manufacture of Sterile Pharmaceutical Products
Point Description of difference Assessment of Difference
Principle Additional explanation
Note referencing EN/ISO Standards for detailed methods for determining microbiological and particulate cleanliness of air, surfaces, etc.
Significant
All Reorganisation of information. Additional information provided. Significant
1 'personnel and /or for equipment and materials.' instead of 'personnel or for goods'. Minor
2 Removed requirement that sterilisation operations are carried out in separate areas within the clean area. Added: 'Manufacturing operations are divided into two categories; firstly those where the product is terminally sterilised, and secondly those which are conducted aseptically at some or all stages.' Minor
3
(3, 4, 19)
Broadened: 'characteristics of air' to 'characteristics of environment'. Air classification table split into particulate (4) and microbial characteristics (19). At rest and in operation limits given.
Explanation of at rest and in operation requirements and relationship.
Description of 4 environmental grades (some reorganisation of existing information in Notes, some new information).
Increased number of permitted particles to align with ISO classifications and reference to EN/ISO 14644-1
Change to laminar flow air speed guidance value from 0.30m/s vertical, 0.45 m/s horizontal to 0.36 - 0.54 m/s at the working position.
Modified requirements (unidirectional flow) added for isolator technology.
Expanded Airborne particulate classification to include at rest and in operation levels.
Requirement for continuous measurement system for monitoring the concentration of particles in the grade A environment, recommended for grade B areas.
Indication for the number of air changes for B, C, D (20ach) removed and related only to room size, equipment and personnel in the room.
Significant
4
(2, Isolator section, 14)
Section rearranged and information re-ordered. Defined short 'clean up period' as 15 to 20 minutes to move from in operation to at rest specifications. 'Closed barrier' section relocated to specific section for isolator technology, points 21 to 25. Significant
(5 to 7) Additional points describing link between GMP air classification system and ISO classification system. Description of monitoring system / devices. Reference to EN/ISO 14644-1. Significant
(8 to 20) Expanded description of requirements and frequency for monitoring of clean room air quality and clean air device monitoring. Significant
5
(17)
Terminally sterilised products:
Preparation of solutions minimum air classification Grade changed from C to D.
Significant
(26, 27) Blow/Fill/Seal Technology:
Section added.
Significant
6
(31 to 35)
Aseptic preparation:
Section expanded. Added requirements for components after washing, transfer requirements for partially closed containers (34).
Removed reference to large and small volume parenterals
Significant
7 to 10
(36 to 39)
Minor wording changes. Minor
11 (44) Redefined areas for which outdoor clothing is prohibited in; from 'the clean areas' to 'changing rooms leading to Grade B & C rooms. Removed reference to disposable clothing. Significant
12 (42) No change. n/a
13 (40) Changed description of cosmetics which can not be worn, to stating that no make-up can be worn. Minor
14 (43) Minor wording changes. Minor
15 (44) Rearrangement of text into point (44). See point 11. Minor
16 (45) Minor wording changes. Broadened description of contamination from particulate contamination to only contamination. Minor
17 to 20
(46 to 49)
Minor wording changes. Minor
21
(50)
Reworded guidance on sinks and drains in grade A/B rooms from 'should be excluded' to 'are prohibited' for areas in which aseptic steps are performed, and other description changes. Significant
22
(51)
Added requirement for the grade of final changing room to be the same as the area to which it leads. Significant
23 (52) Minor wording changes. Minor
24
(53)
Added guidance value for pressure differentials of 10 to 15 Pa (equivalent to EU guide) Significant
25 to 26
(54 to 55)
No / minor wording changes. Minor
27 to 31
(56 to 60)
Minor changes, points 30 and 31 reversed. Minor
32 to 34
(61 to 63)
Added requirement for disinfectants and detergents used within Grade A/B areas to be sterile prior to use. Significant
35 (18) 'Monitoring' specified more clearly; settle plates, volumetric air and surface sampling. Added monitoring of surfaces and personnel after critical operations. Significant
36 to 37
(64 to 65)
Minor wording changes. Minor
38
(66 to 70)
Text describing validation of aseptic processing expanded to include significant extra detail including specifying frequency and scope. Significant
38 to 42
(71 to 74)
Minor wording changes. Minor
43 (75) Removed the statement that fibre generating containers and materials are to be avoided completely when aseptic work is in progress. Minor
(76) Added specific requirement to take measures to minimise particulate contamination of the finished product. Significant
44 to 46
(77 to 79)
No changes. n/a
47 (80) Expanded section on monitoring of bioburden prior to sterilisation. Added reference for parametric release systems. Significant
48
(81)
Added that non-combustible gases should be passed through micro-organism retaining filters. Significant
49 (82) No changes. n/a
50
(83)
Validation of sterilisation procedures to be of particular interest when the method of validation is not stated in the current edition of the European or other Pharmacopoeia to only the EP. Significant
51, 52
(84, 85)
Minor wording changes. 51 - added requirement for biological indicators where appropriate. Significant.
(86) Added requirement for validated loading patterns. Significant
53 (87) Expanded. Minor
54 (88) No change. n/a
(89) Addition of statement regarding sterilisation records, and their release as part of batch release. Significant
55 (90, 91) Point expanded and divided. Minor
56, 57
(92, 93)
No changes. n/a
58
(94)
Rewording to clarify separate (independent) instrumentation for control and monitoring. Moist heat section expanded to include validation of automated systems within moist heat sterilisers. Significant
59 to 76
(95 to 112)
Minor wording and renumbering changes. Minor
77 (113) Integrity test of sterile filters requirement increased from after use to before and after use. Significant
78, 79
(114, 115)
No changes. n/a
(116) New point describing requirements for partially stoppered freeze drying vials. Significant
80 (117) Added that containers closed by fusion must be subject to 100% integrity test. Significant
(118 to 122) New description of requirements for aseptically filled vials and capping processes. Significant
81 (123) No changes. n/a
82 (124) Specified intention of visual check. Added that results of parenteral filled container inspections should be recorded. Minor
83 (125) Addition of requirement of sterility test validation for the products concerned. Significant
(126) Noted that for parametric release validation and process monitoring require special attention. Significant
84
(127)
Minor wording changes. Minor
85 Deleted this point: for injectable products consideration should be given to monitoring the water… Addressed for starting materials. Minor
Table 3: Annexes 2 to 8
NZ Code Annex PIC Annex Title Assessment
Annex 2
8 Sampling of Starting and Packing Materials No differences
Annex 3
10 Manufacture of Pressurised Metered Dose Aerosol Preparations for Inhalation No differences
Annex 4
9 Manufacture of Liquids, Creams and Ointments No differences
Annex 5 11 Computerised Systems No differences
Annex 6
3 Manufacture of Radiopharmaceuticals No differences
Note: Refers to EURATOM directives for basic standards for health protection.
Annex 7 2 Manufacture of Biological Pharmaceutical Products for Human Use No differences.
Annex 8 7 Manufacture of Herbal Pharmaceutical Products No differences.
Table 4: Annex 9 Medicinal Gases (PIC/s Annex 6)
Point Description of difference Assessment of Difference
(1) Addition of title to principle section, reworded, additional guidance regarding the requirements to follow basic requirements of GMP, applicable annexes, pharmacopoeial standards and the annex. Minor
1 (2) Minor rewording. Minor
2 (1) Rearranged into principle section. Minor
3 (2) Added storage to description of operations requiring sufficient space within the premises. Minor
4 Removed requirement to have separate marked areas for different cylinder sizes. Reword stages of manufacture 'awaiting test' to 'quarantine'; 'released' to 'approved'. Minor
(3.2.1) Addition of requirement for validation of manufacture and analysis equipment. Significant
5 (3.2.2) Changed requirements for segregation provided validated automated filling processes are used. Minor
6 (3.2.3) No change. n/a
7 (3.1.1) Addition of potential for campaign filling under validated conditions. Minor
8 (3.2.4) For concurrent filling of medicinal and non-medicinal gases on the same line but different areas, the description 'non-return valve' has changed to 'method of backflow prevention' and the requirement for validation is included. Significant
9 (5.3.2) 'packaging' of cylinders for distribution, including tamper evident seals has been expanded to recommend pressure retentive valves or other protection against empty cylinder contamination. Significant
10 (3.2.5) Expanded explanation to focus on storage tanks and mobile delivery tanks rather than the transportation process. Minor
(4) New documentation section added to detail requirements of batch records etc. Significant
Production and Quality Control sections separated. Minor
(5) Production separated into bulk production and filling and labelling. Significant
(5.1) Added all critical steps in manufacturing should be validated. Significant
(5.2) Added new section title - Bulk production. Minor
(5.2.1) Classification of bulk gases as APIs. Minor
(5.2.2) Addition of documentation specifying the purity, other components, and impurities in the source gas. Flow charts required for manufacturing processes. Significant
(5.2.3) Added optimisation of processes. Minor
(5.2.4) Added validation of computer systems used in controlling / monitoring processes. Significant
(5.2.5) Added requirement for limits for process temperatures, where applicable. Minor
(5.2.6) Added requirement to validate computer systems used in controlling or monitoring processes. Significant
(5.2.7) Added requirement to define a batch for continuous processes. Minor
11 (5.2.8) No change. n/a
(5.2.9) Added microbial quality monitoring for water used for cooling during compression - when in contact with the medicinal gas. Significant
12 (5.2.10) Added that transfer line should have a non-return valve or similar, and that particular attention is paid to appropriate purging. Significant
13 (5.2.11) Removed reference to mixtures of gas. Simplified statement of requirements. Significant
(5.2.12) Added requirement to define a batch, and release for filling against a pharmacopoeial monograph. Minor
(5.3.1) Added requirement to define a filling batch. Minor
14 (5.3.3) Point relocated to filling and labelling section. Added requirement for traceability of cylinders and valves. Significant
15 (5.3.4) Addition of note stressing importance of cleaning and purging post-maintenance or integrity breaches. Minor
16 (5.3.5) Slightly reworded. Added that after assembling a new / tested cylinder the valve should be maintained in a closed position to prevent contamination. Minor
17 (5.3.6) Additional checks prior to filling include a check of residual pressure, setting aside for additional measures in its absence, and removing batch labels. Significant
18 (5.3.7) Rewritten; emphasis on the requirement for care to minimise risk of contamination, addition of maximum theoretical impurity levels for compressed gases, addition of minimum pressure for partial pressurisation prior to purge, addition of criteria for cylinders fitted with residual positive pressure valves. Removal of consideration of cylinder inversion to remove liquid contamination. Significant
19 (5.3.8) Addition of description of temperature as a potential indicator that cylinders have been filled. Minor
(6) Added Quality Control section. Minor
(6.1) Added specification and testing of water used for hydrostatic testing. Significant
(6.2) Added requirement to test and release gases against specifications. Full monograph testing to be performed at a sufficient frequency to assure ongoing compliance. Significant
(6.3) Added that the bulk gas should be released for filling. Minor
20 (6.4) Replaced 'purity' with 'assay and if necessary water content'. Minor
21 (6.5) Unchanged. n/a
22 & 23
(6.6 & 6.7)
Point 22 combined with the first part of point 23 into point 6.6; changes to required test regime for two or more gases, reference to balance gas when mixing 3 gases. Second part of point 23 renumbered as 6.7. Minor
24 (6.8) No change. n/a
25 (6.9) Addition of application of tamper proof seal after leak-testing. Added requirement for leak testing to be performed after testing. Minor
26 (6.10) Minor wording changes. Minor
27 (6.11) Minor wording changes, addition of periodic testing of the conformance of gas held within cryogenic vessels retained by customers against pharmacopoeial requirements. Significant
28 (6.12) No change. n/a
29 (5.3.9) Added the filling date and expiry date to the batch number as information which may be listed on a separate label. Minor
30 (7.1) Change from qualified person to authorised person. Minor
31 (7.2) Added ' to ensure cylinders remain clean up to the time of use'. Significant
32 (7.3) '…and permit rotation of stock on a FIFO basis.' instead of '…and permit rotation of stock.' Minor
(7.4) Additional requirement for specific conditions for storage and transportation for gas mixtures for which phase separation occurs on freezing. Significant
Added glossary
Table 5: Guidelines for the Manufacture of Active Pharmaceutical Ingredients

Note: There are substantial differences between the New Zealand Guidelines for APIs (no annex reference) and the current PIC/s Guide. Substantial areas of change are summarised briefly under the PIC/s Guide chapter heading. Note that this summary is intended as a guide only. Manufacturers’ representatives should make a full, independent assessment on which to base submissions.

Chapter Heading Description of difference
Table 1 Description of applicability of the guide to various types of manufacture.
Quality Management Added product quality review.
Personnel Expanded existing concepts. Added section on consultants.
Buildings and Facilities Added potential for 'closed' equipment to be located outside. Added separation of laboratories from production areas.
Process Equipment Added requirements for computerised systems
Documentation and Records Significantly greater description of specific requirements for procedures and records. Expanded requirements for batch records (and masters), laboratory records
Materials Management Introduced supplier evaluation and approval by quality department, sampling and testing, added re-evaluation point.
Production and In-process Controls Added reference to reprocessing / reworking, blending batches of APIs, expanded requirement for cleaning validation.
Packaging… New sections on label issuance and control, and packing / labelling operations.
Storage and Distribution New section.
Laboratory Controls Greatly expanded from section 7.1; new stability, expiry and retest dating sections.
Validation Although validation was referenced in the NZ Guide, further guidance for manufacturers is provided.
Change Control New section.
Rejection and Re-use of Materials New section.
Complaints and Recalls New section.
Contract Manufacturers (Including Laboratories) New section.
Agents, Brokers… New section.
Specific Guidance … Cell Culture / Fermentation New section.
APIs for use in Clinical Trials New section.
Glossary New section.
PIC/S Definition of "medicinal product"

For the purpose of this Scheme "medicinal product" means:
(a) any pharmaceutical, medicine or similar product intended for human or veterinary use which is subject to control by health legislation in the manufacturing Country or in the importing Country, and
(b) any active pharmaceutical ingredient which the manufacturer uses in the manufacture of a product referred to in sub-paragraph (a) above

EU Definition of "medicinal product" from Directive 2001/83/EC Article 1(2)

Any substance or combination of substances presented for treating or preventing disease in human beings. Any substance or combination of substances which may
be administered to human beings with a view to making a medical diagnosis or to restoring, correcting or modifying physiological functions in human beings is likewise considered a medicinal product.

In New Zealand, the legal meaning of ‘medicine’ continues to be derived from the Medicines Act 1981.

 

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