Revised: 2 July 2013
Consultations
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.
