2013 editions of the PIC/S Guide to GMP Version 1.0, May 2013 About the Therapeutic Goods Administration (TGA) The Therapeutic Administration (TGA) is part of the Australian Government Department of Health and Ageing, and is responsible for regulating medicines and medical devices. The TGA administers the Therapeutic Goods Act 1989 (the Act), applying a risk management approach designed to ensure therapeutic goods supplied in Australia meet acceptable standards of quality, safety and efficacy (performance), when necessary. The work of the TGA is based on applying scientific and clinical expertise to to ensure that the benefits to consumers outweigh any risks associated with the use of medicines and medical devices. The TGA relies on the public, healthcare professionals and industry to report problems with medicines or medical devices. TGA investigates reports received by it to determine any necessary regulatory action.
4.2 Documents should be designed, prepared, reviewed, and distributed with care. They should comply with the relevant parts of Product Specification Files, Manufacturing and Marketing Authorisation dossiers, as appropriate. The reproduction of working documents from master documents should not allow any error to be introduced through the reproduction process. 4.2 Documents should be designed, prepared, reviewed and distributed with care. They should comply with the relevant parts of the manufacturing and marketing authorisation dossiers. Providing additional guidance; First sentence has been moved from clause 4.3; Last sentence has been moved from clause 4.4 4.3 Documents containing instructions should be approved, signed and by appropriate and authorised persons. [Documents should have unambiguous contents and be uniquely identifiable.] The effective date should be defined. 4.3 Documents should be approved, signed and dated by appropriate and authorised persons. Providing additional guidance; Second sentence of 4.3 has been moved from 4.4; Only the definition of effective date is a new inclusion Minor 4.4 Documents containing instructions should be laid out in an orderly fashion and be easy to check. The style and language of documents should fit with their intended use. Standard Operating Procedures, Work Instructions and Methods should be written in an imperative mandatory style. 4.4 Documents should have unambiguous contents; title, nature and purpose should be clearly stated. They should be laid out in an orderly fashion and be easy to check. Reproduced documents should be clear and legible. The reproduction of working documents from master documents Providing additional guidance; Last sentence of 4.4 has been moved to 4.2 Nil
new data. Justification for this should be documented and should take into account the requirements for retention of batch documentation; for example, in the case of process validation data, the accompanying raw data should be retained for a period at least as long as the records for all batches whose release has been supported on the basis of that validation exercise. The following section gives some examples of required documents. The quality management system should describe all documents required to ensure product quality and patient safety. 4.13 There should be appropriately authorised and dated specifications for starting and packaging materials, and finished products. 4.10 should be appropriately authorised and dated specifications for starting and packaging materials, and finished products; where appropriate, they should be also available for intermediate or bulk products. Requirement for specs for all intermediates and bulks has been deleted as 4.15 now allows for a risk based approach to this requirement Nil 4.14 Specifications for starting and primary or printed packaging materials should include or provide reference to, if applicable: A description of the materials, including: The designated name and the internal code reference; 4.11 Specifications for starting and primary or printed packaging materials should include, if applicable: A description of the materials, including: The designated name and the internal code reference; Inclusion of an option to put references in specifications Nil
A description of the packaging operation, including any significant subsidiary operations, and equipment to be used; Details of in-process controls with instructions for sampling and acceptance limits. 4.20 A Batch Processing Record should be kept for each batch processed. It should be based on the relevant parts of the currently approved Manufacturing Formula and Processing Instructions, and should contain the following information: The name and batch number of the product; Dates and times of commencement, of significant intermediate stages and of completion of production; Identification (initials) of the operator(s) who performed each significant step of the process and, where appropriate, the name of any person who checked these operations; The batch number and/or analytical control number as well as the quantities of each starting material actually weighed (including the batch number and amount of any recovered or reprocessed material added); Any relevant processing operation or event and major equipment used; 4.17 A Batch Processing Record should be kept for each batch processed. It should be based on the relevant parts of the currently approved Manufacturing Formula and Processing Instructions. The method of preparation of such records should be designed to avoid transcription errors. The record should carry the number of the batch being manufactured. Before any processing begins, there should be recorded checks that the equipment and work station are clear of previous products, documents or materials not required for the planned process, and that equipment is clean and suitable for use. During processing, the following information should be recorded at the time each action is taken and, after completion, the record should be dated and signed in agreement by the person responsible for the processing operations: the name of the product; dates and times of commencement, of significant intermediate stages and of completion of production; name of the person responsible for each stage of production; Moved the second paragraph of PE 009-8 clause 4.17 to PE clause 4.18 as a new entry f), as this is a more logical place Minor rewrite replacing PE 009-8 clause 4.17 entry c) by PE 009-10clause 4.20 entry i). That is, replacing names of responsible persons per stage of production with one name of the person Nil
A record of the in-process controls and the initials of the person(s) carrying them out, and the results obtained; The product yield obtained at different and pertinent stages of manufacture; Notes on special problems including details, with signed authorisation for any deviation from the Manufacturing Formula and Processing Instructions; Approval by the person responsible for the processing operations. Note: Where a validated process is continuously monitored and controlled, then automatically generated reports may be limited to compliance summaries and exception / out-of-specification (OOS) data reports. initials of the operator of different significant steps of production and, where appropriate, of the person who checked each of these operations (e.g. weighing); the number and/or analytical control number as well as the quantities of each starting material actually weighed (including the batch number and amount of any recovered or reprocessed material added); any relevant processing operation or and major equipment used; a record of the in-process controls and the initials of the person(s) carrying them out, and the results obtained; the amount of product yield obtained at different and pertinent stages of manufacture; on special problems including details, with signed authorisation for any deviation from the Manufacturing Formula and Processing Instructions. responsible for the operations Inclusion of a provision for automated reporting systems 4.21 A Packaging Record should be kept for each batch or part batch processed. It should be based on the relevant parts of the Packaging Instructions. The batch packaging record should contain the following information: The name and batch number of the product; 4.18 A Batch Packaging Record should be kept for each batch or part batch processed. It should be based on the relevant parts of the Packaging Instructions and the method of preparation of such records should be designed to avoid transcription errors. The record should carry the batch number and the quantity of bulk product to be packed, as well as the batch number and the planned quantity of finished product that will be obtained. Moved the second paragraph of PE 009-8 clause 4.18 to PE clause 4.19 as a new entry f), as Nil trial
taken or conclusions reached, where appropriate, for the following examples: Validation and qualification of processes, equipment and systems; Equipment assembly and calibration; Technology transfer; Maintenance, cleaning and sanitation; Personnel matters including signature lists, training in GMP and technical matters, clothing and hygiene and verification of the effectiveness of training; Environmental monitoring; Pest control; Complaints; Recalls; Returns; Change control; Investigations into deviations and Internal quality/GMP compliance audits; Summaries of records appropriate (e.g. product quality review); Supplier audits. validation; equipment assembly and calibration; maintenance, cleaning and sanitization; personnel matters including training, clothing, hygiene; environmental monitoring; pest control; complaints; recalls; returns requirement to have those documents is not new, as performing and recording those activities was already required elsewhere in the Guide to GMP, only the fact that a document was required to do so wasn’t mentioned in this clause yet trial
well as with other relevant national requirements. [1. The manufacturing and handling of radiopharmaceuticals is potentially hazardous. The level of risk depends in particular upon the types of radiation, the energy of radiation and the half-lives of radioactive isotopes. Particular attention must be paid to the prevention of cross-contamination, to the retention of radionuclide contaminants, and to waste disposal.] New clause in PE009-10 However, this is almost identical from the principle in PE009-8: PRINCIPLE “The manufacturing and handling of radiopharmaceuticals is potentially hazardous. The types of radiation emitted and the half-lives of the radioactive isotopes are parameters contributing to the level of risk. Particular attention must be paid to the prevention of cross-contamination, to the retention of radionuclide contaminants, and to waste disposal” None, the clause is a statement. Nil 2. Due to shelf-life of their radionuclides, some radiopharmaceuticals may be released before completion of all quality control tests. In this case, the exact and detailed description of the whole release procedure including the responsibilities of the involved personnel and the continuous assessment of the effectiveness of the quality assurance system is essential. New clause in PE009-10 However, this is almost identical wording from the principle in PE009-8. The term “shelf-life” has replaced “half-life”: PRINCIPLE “Due to their short half-life, some radiopharmaceuticals are released before completion of certain Quality Control tests. In this case, the continuous assessment of the effectiveness of the Quality Assurance system becomes very important.” None, the clause is a statement. Nil 3. This guideline is applicable to manufacturing procedures employed by industrial manufacturers, Nuclear Centres/Institutes and PET Centres for the production and quality control of the following types of products: New clause – no equivalent in Providing additional clarification on applicability of the GMP Guide to Nil
16. Radioactive products should be manufactured in controlled (environmental and radioactive) All manufacturing steps should take place in self-contained facilities dedicated to radiopharmaceuticals. New clause, but comments are identical in intent to those in PE009-8 Annex 3 clause 2: “Radioactive products should be stored, processed, packaged and controlled in dedicated and self-contained facilities. Equipment used for manufacturing operations should be reserved for radiopharmaceuticals.” The requirements for controlled environments echo those outlined in existing clause 3.12. None Nil 17. Measures should be established and implemented to prevent from personnel, materials, radionuclides etc. Closed or contained equipment should be used whenever appropriate. Where open equipment is used, or equipment is opened, precautions should be taken to minimize the risk of contamination. The risk assessment should demonstrate that the environmental cleanliness level proposed is suitable for the type of product being manufactured. New clause, but comments are identical in intent to those in PE009-8 clauses 5.18-5.19. Specific requirement for Risk assessment to justify environmental control used for manufacture. This is in line with existing QRM principles, and is not an additional requirement. Minor 18. Access to the manufacturing should be via a gowning area and should be restricted to authorised personnel. New clause, but comments are identical in intent to those in PE009-8 clauses 3.5, 3.7, 3.31 & 5.16. This statement specifically mentions the use of separate gowning areas Minor trial.
34. Production of different radioactive products in the same working area (i.e. hot-cell, LAF unit), at the same time should be avoided in order to minimise the risk of cross-contamination or mix-up. 6. Production of different radioactive products in the same work stations and at the same time should be avoided in order to minimise the risk of cross contamination or mix-up. None Nil 35. Special attention should be paid to validation including validation of computerised systems which should be carried out in accordance in compliance PIC/S GMP Guide, Annex 11. New manufacturing processes should be validated prospectively. New clause, but comments are identical in intent to in PE009-8 clause 5.21-5.24 and Annex 11. None Nil 36. The critical parameters should normally be identified before or during validation and the ranges necessary for reproducible operation should be defined. New clause, but comments are identical in intent to those in PE009-8 Annex 15 clauses 24-25. Approach to validation is similar to the QBD principle, however, manufacturers with good sound validation principles should not be challenged by this clause. Nil 37. Integrity testing of the membrane filter should be performed for aseptically filled products, taking into account the need for radiation protection and maintenance of filter sterility. New clause, but comments are identical in intent to those in PE009-8 Annex 1 clause 113. None Nil 38. Due to radiation exposure it is accepted that most of the labelling of the direct container, is done prior to manufacturing. Sterile empty closed vials may be labelled with partial information prior to filling New clause – no equivalent in This clause outlines the practical Nil
40. Most radiopharmaceuticals are intended for use within a short time and the period of validity with regard to the radioactive shelf-life, must be clearly stated. New clause, but comments are identical in intent to those on ongoing stability in PE009-8 clauses 6.23-6.33 None Nil 41. Radiopharmaceuticals having radionuclides with long should be tested to show, that they meet all relevant acceptance criteria before release and certification by the Authorised Person. New clause – no equivalent in PE009-8 No change, it is TGA policy to expect testing in accordance with the release specification to release. No impact on existing manufacturers; however, TGA should define “long half-life” Nil. 42. Before testing is performed samples can be stored to allow sufficient radioactivity decay. All tests including the sterility test should be performed as soon as possible. New clause – no equivalent in PE009-8 This clause clarifies current practices. No change for industry. Nil 43. A written procedure detailing the assessment of production and analytical data, which should be considered before the batch is dispatched, should be established. New clause, but comments are identical in intent to those on release in PE009-8 clause 4.24. Complements Annex 3clause 39 None Nil
information to the clinical coordinator or equivalent if required. 47. A system to verify the quality of starting materials should be in place. Supplier approval should include an evaluation that provides adequate assurance that the material consistently meets specifications. The starting materials, packaging materials and critical process aids should be purchased from approved suppliers. New clause, but comments are identical in intent to in PE009-clauses 8 5.25 & 5.26. Complements PE009-10 Annex 3 clause 30 None Nil 48. For radiopharmaceuticals sufficient samples of each batch of bulk formulated product should be retained for at least six months after expiry of the finished medicinal product unless otherwise justified through risk management. Annex 3 clause 9 PE009-8 “Unless otherwise specified in the marketing authorisation, reference samples of every batch should be retained.” New clause, but comments are identical in intent to those in PE009-8 Annex 19 clause 2.2 & 3.1 – 3.2. The retention period for is shorter than that for non radio materials (12 months past expiry). Clause allows risk management to determine whether any bulk retain sample will be kept. Manufacturer will have to possibly devise risk assessments and amend Minor
purposes on manifolds dedicated to medicinal gases may be acceptable if justified and performed under control. In these cases, the quality of the non-medicinal gas should be at least equal to the required quality of the medicinal gas and GMP standards should be maintained. Filling should then be carried out by campaigns. 15. Repair and maintenance operations (including cleaning and purging) of equipment, should not adversely affect the quality of the medicinal gases. In particular, procedures should describe the measures to be taken after repair and maintenance operations involving breaches of the system’s integrity. Specifically it should be demonstrated that the equipment is free from any contamination that may adversely affect the quality of the finished product before releasing it for use. Records should be maintained. 16. A procedure should describe the measures to be taken when a tanker is back into medicinal gas service (after transporting non-medicinal gas in the conditions mentioned in section 12, or after a maintenance operation). This should include analytical testing. gas provided that the quality of the latter is at least equal to the quality of the medicinal gas. DOCUMENTATION 17. Data included in the records for each batch of cylinders / mobile cryogenic vessels must ensure that each filled cylinder is traceable to significant aspects of the relevant filling operations. As appropriate, the following should be entered: the name of the product; batch number; 4. Documentation 4.1 Data included in the records for each batch of cylinders filled must ensure that each filled cylinder is traceable to significant aspects of the relevant filling operations. As appropriate, the following should be entered: the name of the product; the date and the time of the filling operations; Addition of some parameters to the list of parameters to be recorded: Inclusion of a shortened similar list for deliveries of bulk Minor
controlled according to specifications and approved for filling. 23. In the case of continuous processes as those mentioned in ‘Principle’, there should be adequate controls to ensure that the gas complies with specifications. 24. Cylinders, mobile cryogenic vessels and valves should conform to appropriate technical specifications and any relevant requirements of the Marketing Authorisation. They should be dedicated to a single medicinal gas or to a given mixture of medicinal gases. Cylinders should be colour-coded according to relevant standards. They should preferably be fitted with minimum pressure retention valves with non-return mechanism in order to get adequate protection against contamination. 25. Cylinders, mobile cryogenic vessels and valves should be checked before first use in production, and should be properly maintained. Where medical devices have gone through a conformity assessment procedure , the maintenance should address the medical device manufacturer’s instructions. 26. Checks and maintenance operations should not affect the quality and the safety of the medicinal product. The used for the hydrostatic pressure testing carried out on cylinders should be at least of drinking quality. 27. As part of the checks and maintenance operations, cylinders should be subject to an internal visual inspection before fitting the valve, to make sure they are not 5.2.5 If applicable, limits for process temperatures should be documented and in-process monitoring should include temperature measurement. 5.2.6 Computer systems used in controlling or monitoring processes should be validated. 5.2.7 For continuous processes, a definition of a batch should be documented and related to the analysis of the bulk gas. 5.2.8 Gas production should be continuously monitored for quality and impurities. 5.2.9 used for cooling during compression of air should be monitored for microbiological quality when in contact with the medicinal gas. 5.2.10 All the transfer operations, including controls before transfers, of liquefied from primary storage should be in accordance with written procedures designed to avoid any contamination. The transfer line should be equipped with a non-return valve or any other suitable alternative. Particular attention should be paid to purge the flexible connections and to coupling hoses and connectors. 5.2.11 Deliveries of gas may be added to bulk storage tanks containing the same gas from previous deliveries. The results of a sample must show that the quality of the delivered gas is acceptable. Such a sample could be taken from the delivered gas before the delivery is added; or from the bulk tank after adding and mixing.
if the cylinder is fitted with a minimum pressure retention when there is no signal indicating there is a positive residual pressure, the correct functioning of the valve should be checked, and if the valve is shown not to function properly the cylinder should be sent to maintenance, if the cylinder is not fitted with a minimum pressure retention valve, when there is no positive residual pressure the cylinder should be put aside for additional measures, to make sure it is not contaminated with water or other contaminants; additional measures could consist of internal visual inspection followed by cleaning using a validated method; a check to ensure that all previous batch labels have been removed; a check that any damaged product labels have been removed and replaced; a visual external inspection of each cylinder, mobile cryogenic vessel and for dents, arc burns, debris, other damage and contamination with oil or grease; cleaning should be done if necessary; a check of each cylinder or mobile cryogenic vessel outlet connection to determine that it is the proper type for the particular gas involved; 5.3.5 Cylinders should be subject to an internal visual inspection when they are new in connection with any hydrostatic pressure test or equivalent test. After fitting of the valve, the valve should be maintained in a closed position to prevent any contamination from entering the cylinder. 5.3.6 Checks to be performed before filling should include: a to determine the residual pressure (>3 to 5 bar) to ensure that the cylinder is not emptied; Cylinders with no residual pressure should be put for additional measures to make sure they are not contaminated with water or other contaminants. These could include cleaning with validated methods or visual inspection as justified; Assuring that all batch labels and other labels if damaged have been removed; visual external inspection of each valve and container for dents, arc burns, debris, other damage and contamination with oil or grease; Cylinders should be cleaned, tested and maintained in an appropriate manner; a check of each cylinder or cryogenic vessel valve connection to determine that it is the proper type for the particular medicinal gas involved;
activity, these constituents must also be specified and quantitatively determined. If a herbal remedy contains several vegetable drugs or preparations of several vegetable drugs and it is not possible to perform a quantitative determination of each active ingredient, the determination may be carried out jointly for several active ingredients. The need for this procedure must be justified. Annex 11 – Computerised systems PE 009-10 PE 009-08 Nature of impact Estimated significance of impact Principle This annex applies to all forms of computerised systems used as part of a GMP regulated activities. A computerised system is a set of software and hardware components which together fulfil certain functionalities. The application should be validated; IT infrastructure should be qualified. Principle The introduction of computerised systems into systems of manufacturing, including storage, distribution and quality control does not the need to observe the relevant principles given elsewhere in the Guide. Where a computerised system replaces a manual operation, there should be no resultant decrease in product quality or quality assurance. Consideration should be given to the risk Rewrite highlighting the pre-existent requirement to validate computerised systems and qualify IT infrastructure Minor
processing, formal agreements must exist between the manufacturer and any third parties, and these agreements should include clear statements of the responsibilities of the third party. IT-departments should be considered analogous. 3.2 The competence and reliability of a supplier are key factors when selecting a product or service provider. The need for an audit should be based on a risk assessment. 3.3 Documentation supplied with commercial off-the-shelf products should be reviewed by regulated users to check that user requirements are fulfilled. 3.4 Quality system and audit information relating to suppliers or developers of software and implemented systems should be made available to inspectors on request. 18 When outside agencies are used to provide a computer service, there should be a formal agreement including a clear statement of the responsibilities of that outside agency (see Chapter 7). existing requirements; Updating text to developing computer technology standards Validation 4.1 The validation documentation and reports should cover the relevant steps of the life cycle. Manufacturers should be able to justify their standards, protocols, acceptance criteria, procedures and records based on their risk assessment. 4.2 Validation documentation should include change control records (if applicable) and reports on any deviations observed during the validation process. 4.3 An up to date listing of all relevant systems and their GMP functionality (inventory) should be available. 2. The extent of validation necessary will depend on a number of factors including the use to which the system is to be put, whether it is prospective or retrospective and whether or not novel elements are incorporated. Validation should be considered as part of the complete life cycle of a computer system. This cycle includes the stages of planning, specification, programming, testing, commissioning, documentation, operation, monitoring and changing. 3. A written detailed description of the system should be produced (including diagrams as appropriate) and kept up to date. It should describe the principles, objectives, security measures and scope of the system and the main Clarification of requirements; Providing further detail on existing requirements; Updating text to developing computer technology and standards
Data 5. Computerised systems exchanging data electronically with other systems should include appropriate built-in checks for the correct and secure entry and processing of data, in order to minimize the risks. 6. The system should include, where appropriate, built-in checks of the correct entry and processing of data. Clarification of requirements; Providing further detail on existing requirements; Nil Accuracy checks 6. For critical data entered manually, should be an additional check on the accuracy of the data. This check may be done by a second operator or by validated electronic means. The criticality and the potential consequences of erroneous or incorrectly entered data to a system should be covered by risk management. 8. Data should only be entered or amended by persons authorised to do so. Suitable methods of deterring unauthorised of data include the use of keys, pass cards, personal codes and restricted access to computer terminals. There should be a defined procedure for the issue, cancellation, and alteration of authorisation to enter and amend data, including the changing of personal passwords. Consideration should be given to systems allowing for recording of attempts to access by unauthorised persons. 9. When critical data are being entered manually (for example the weight and batch number of an ingredient during dispensing), there should be an additional check on the accuracy of the record which is made. This check may be done by a second operator or by validated electronic means. Reduction of prescriptive character of requirements; Clarification of requirements Minor Data storage 7.1 Data should be secured by both physical and electronic means against damage. Stored data should be 14. Data should be protected by backing-up at regular intervals. Back-up data should be stored as long as necessary at a separate and secure location. Clarification of requirements Minor trial trial
An investigational medicinal product must exist before a process can be defined as reconstitution. The process of reconstitution has to be undertaken as soon as practicable before administration. This process has to be defined in the clinical application / IMP dossier and clinical protocol, or related document, available at the site. Glossary: no changes, from the fact that the definitions of ‘Immediate packaging’ and ‘Outer packaging’ from PE 009-8 have been deleted in PE 009-10 as in practice these two terms were perceived as confusing because for non-investigational medicinal products the terms ‘primary packaging’ and ‘secondary packaging’ are commonly used Nil Nil Clauses 1 and 2: no change 3. All personnel involved with investigational medicinal products should be appropriately trained in the requirements specific to these types of product. Even in cases where the number of staff involved is small, there should be, for each batch, separate people responsible for production and quality control. 4. The Authorised Person should ensure that there are systems in place that meet the requirements of GMP and have a broad knowledge of pharmaceutical development and clinical processes. Guidance for the Authorised Person in connection with the certification of investigational medicinal products is given in paragraphs 38 to 41. 3. All personnel involved with investigational medicinal products should be appropriately trained in the requirements specific to types of product. 4. The Authorised Person should in particular be responsible for ensuring that there are systems in place that meet the requirements of this Annex and should therefore have a broad knowledge of pharmaceutical development and clinical processes. Guidance for the Authorised Person in connection with the certification of investigational medicinal products is given in paragraphs 38 to 41. Additional clarification on situations of staff numbers, which was already required based on GMP Chapter 2; Correction of error changing ‘Annex’ into ‘GMP’ Nil