When it was current, I reviewed the Australian code of good manufacturing practice for medicinal products (16 August 2002) so I was aware of the pertinent details in relation to viable environmental monitoring and testing.

The Australian Code of Good Manufacturing Practice for Medicinal Products 2002 was revoked effective from 1 July 2010 and replaced by the PICS Guide for Good Manufacturing Practice for Medicinal Products 2009, as adopted in Therapeutic Goods (Manufacturing Principles) Determination No. 1 of 2009. The 2002 GMP Code for Medicinal Products remains available here for comparison purposes.

For historical interest, my review of the Australian Code of GMP review is attached.

Both the revoked 2002 Australian GMP code and the 2009 PICs guide are based on ICH Q&A Good Manufacturing practice Guide for Active Pharmaceutical Ingredients which was last modified in 2000.  In 2015 21 pages worth of clarifications were published to clear up some technical questions and to remove ambiguities.  Looking at them, I’m not sure why clarification was needed as they all seem straight forward and answerable by anyone experienced working within a pharmaceutical manufacturing environment.  This means that despite having “no recent experience” as deemed by some potential employers, my knowledge is still bang up to date. Combine that with my fantastic memory and I’m a catch.

Aust code of GMP for Medicinal Products (16 Aug 2002)

ICH Q7A Guidance

Notes on AUSTRALIAN CODE OF GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS 16 August 2002

The points that follow are related to microbiology.

Should = must.

CHAPTER 1

Basic requirements of GMP:

• Adequate qualification and training
• Adequate premises and space
• Suitable equipment and services
• Correct materials, containers labelling
• Approved procedures/instructions
• Unambiguous and clear instructions are written and followed
• Records of everything are to be made – deviations are to be fully recorded and investigated

Quality Control

• Relevant tests to be carried out
• No products release for sale until approved by QC
• Validated test methods
• Records made of all equipment used, tests, inspections, procedures
• Sufficient samples held for future (complete) examination of product where required

 

CHAPTER 2

Personnel

• Sufficient number of trained personnel
• Responsibilities:
  • clearly understood and recorded
  • not overwhelming resulting in risk to quality
  • no (unexplained) gaps or overlaps in responsibilities between personnel
  • head of production and head of quality control to be separate entities

Personal Hygiene

• detailed hygiene programs required
• procedures must be followed to the letter
• medical exam required upon recruitment and then as necessary
• no person with an infectious disease or open legions (on exposed surface of skin) to be involved in manufacturing of products

 

CHAPTER 3

Production Area

• surfaces to be smooth, free from crack or ledges and allow for easy cleaning
• dust generating activities need procedures to prevent cross contamination

Storage Areas

• rejected, returned or recalled product to be stored separately to other products

Quality Control Areas

• separated from production areas – particularly for microbiology lab

Ancillary Areas

• rest/refreshment rooms separated from other areas
• appropriate for number of personnel using area
• Where parts stored in production, rooms or lockers are required dedicated for the equipment

Equipment

• Designed for easy and through clean
• Stored in clean and dry condition
• Fixed pipe work needs contents labelling and direction of flow indicators
• WFI and distilled piping needs written sanitisation procedures
• Defective equipment needs to be removed (or clearly labelled as defective)

 

CHAPTER 4

Documentation

• Should prevent errors from spoken communication
• Detailed procedures for use of electronic storage systems needed and accuracy of records must be checked
• Data must be readily available throughout period of retention

Manufacturing Formula and Processing Instructions

• Formally authorised instructions for batch formulation and processing required for every batch

Batch Processing Records

• Recorded checks indicating equipment is clean and suitable for use

Batch packing Records

• Recorded checks indicating equipment is clean and suitable for use

 

CHAPTER 5

Production – general

• Damage to containers that may affect product quality need to be investigated and reported to QC
• Pipelines and equipment need to be connected correctly (and checked that this is so)
• Deviations need to be approved in writing with QC involvement

Prevention of Cross Contamination

• Products in which contamination is likely to be most significant are those administered by injection
• Avoid by separating via area or time

Validation

• Significant amendments to manufacturing process require validation

Packaging Operations

• Different products (batches) not to be packaged in close proximity to other products
• Any discrepancy observed during reconciliation of bulk product / packaging materials and units produced required investigation and satisfactory accounting for prior to release of product to market

Rejected, Recovered and Returned Materials

• Recovery of all or part of earlier batches required prior authorisation and must be documented
• Products returned from the market must be destroyed is fill documented storage and transport history does not exist

 

CHAPTER 6

Quality Control

• The independence of Quality Control from production is considered fundamental to the satisfactory operation of Quality Control.

Documentation

• QC documentation relating to a batch records must be retained for 1 year after the batch expiry date
• For some data, records to be kept in manner allowing trend evaluation
• Lab notebooks and records must be retained and readily available

Sampling

• Reference samples of finished product to be retained til 1 year past expiry of batch
• Reference samples of a sufficient size to permit a full re-examination

 

ANNEX 1

Manufacture of Sterile Medicinal Products

• Sole reliance for sterility or other quality aspects should not be placed on terminal process of finished product test
• ISO5 – grade A and B – Class 100
• ISO7 – grade C – Class 10 000
• ISO8 – grade D – Class 100 000
• In order to control the microbiological cleanliness of the various grade in operation, the areas should be monitored
• Surfaces and personnel should be monitored AFTER critical operations
• Additional monitoring is required after validation and cleaning
• Appropriate alert and action limits need to be set and documented corrective action proscribed for breach of limits

Isolator Technology

• The air classification for the background environment should be at least grade D
• Monitoring to be carried out routinely and include frequent leak rate testing of isolator and glove/sleeve system

Terminally Sterilised Products

• Preparation of components to be done in at least grade D
• Where product to be held for a long time, or supports growth of microbes, preparation to be done in at least grade C
• Filling in at least grade C
• Where product supports growth, is or exposed for > a few seconds, filling to be done in grade A with at least grade C background

Personnel

• Only minimum number of personnel required should be present in clean area
• High standards of personal hygiene are essential
• Wristwatches, makeup and jewellery not to be worn in clean areas
• Protective clothing in grade A/B should shed virtually no fibres or particulate matter and retain particles shed by body
• Outdoor clothing should not be brought into change rooms leading to grade B and C rooms

Premises

• Smooth unbroken surfaces free from ledges or uncleanable recesses
• False ceilings to be sealed
• Pipes installed to not create recesses
• Change rooms to be designed as airlocks
• Hand washing facilities to be only in the first stage of the changing rooms
• Airlock doors not be opened simultaneously
• Adjacent rooms with different grades to have a 10-15 pascal differential
• Air flow patterns to be demonstrated to not present contamination risk from particle generating person, machine or operation to a zone of higher product risk
• Pressure differences to be recorded regularly or otherwise documented

Equipment

• Conveyor belts not to pass from grade A to lower classification area unless sterilised continually
• Equipment and fitting to be installed in manner allowing maintenance and repair to be performed outside the clean area
• After maintenance in clean area, area to be cleaned/sanitised to restore area to clean state before processing recommences
• Water treatment plates should not operate beyond capacity
• WFI to be produced and stored in manner preventing microbial growth

Sanitation

• Clean areas to be cleaned in accordance to written procedure
• >1 type of disinfectant to be employed (when used)
• regular monitoring to detect development resistant strains

Processing

• precautions required to minimise contamination at all stages prior to sterilisation
• validation of aseptic processing by media trials
  • imitate actual processing as closely as possible including
    • interventions
    • worst case interventions
  • run x2/year per shift and process
  • any contamination to be investigated
• water sources, treatment equipment and treated water to be monitored regularly – records to be kept of results and of any action taken
• activities in clean room to be kept to a minimum and involve controlled methodical movements
• ambient temperature and humidity not uncomfortably high
• microbiological contamination of starting materials to be minimal
• interval between washing and drying to sterilisation to be minimal and proscribed
• time between start of solution preparation and sterilisation or filtration through a microbe retaining filter to be minimised – maximum permissible time to be proscribed
• bioburden to be monitored prior to sterilisation
• all solutions to be passed through a microbe retaining filter, sited if possible immediately before filling
• any article required in a clean area to be sterilised and passed into the clean area though double ended sterilisers sealed into the wall, or by procedure not introducing contamination (if sterilisation not possible)
• any new procedure to be validated and validation verified at schedule intervals

Sterilisation

• All sterilisation processes should be validated
• The validity of the process to be validated at scheduled intervals, at least annually
• Validated loading pattered required
• Clear means to differentiate sterilised and non sterilised products required
• Sterilisation records required for each sterilisation run and approved as part of batch release

Sterilisation By Heat

• Each heat sterilisation cycle should be recorded on a time/temperature chart
• Precautions to be taken against contamination of sterilised load during cooling – cooling fluid or gas in contact with product to be sterilised

Moist Heat

• Both temperature and pressure used to monitor process
• Control instruments separated from recording instruments
• Reading of independent temperature indicator to be routinely checked against the chart recorder during sterilisation period
• Frequent leak tests on the chamber when a vacuum phase is part of the cycle
• Steam used for sterilisation of a suitable quality free of additives that may contaminate the product or equipment

Dry heat

• The process used should include air circulation within the chamber and the maintenance of a positive pressure
• Any air admitted to the chamber should be passed through a HEPA filter
• Where process used to remove pyrogens, endotoxin challenge tests required as part of validation

Sterilisation by Radiation

• Radiation dose should be measured
• Total dose to be administered within proscribed time period

Sterilisation with Ethylene Oxide

• Only use this method when all else is impracticable
• Each sterilisation run to be monitored with biological indicators and for cycle time, pressure, temperature, humidity, gas concentration and total gas used and record of this to form part of batch record

Filtration of Medicinal Products which cannot be sterilised in their Final Container

• Filtration alone is not considered sufficient when sterilisation in the final container is not possible
• Consideration to be given to complimenting the filtration process with some degree of heat treatment
• A second filtration using an additional sterilised microbe retaining filter, immediately prior to filling may be advisable
• Final filtration to be carried out as close to point of filling as practicable
• Fibre shedding characteristics of filters to be minimal
• Integrity of sterilised filter to be verified before and after use
• Time taken to filter known quantity of bulk solution and the pressure difference required across the filter to be determined during validation and any significant difference to be noted, investigated and the results to be included in the batch record.

Finishing of Sterile Products

• Container closed by fusion (amps) subject to 100% integrity testing
• Container sealed under vacuum to be tested for maintenance of vacuum after pre-determined time period
• Filled container to be individually inspected for extraneous contamination or defects

Quality Control

• The sterility test only regarded as the last in series on control measures to ensure sterility and must be validated for the product(s) concerned
• Samples taken for sterility testing to represent whole batch, including samples taken from most at risk section of batch
  • For aseptically filled products: beginning, end and after significant intervention
  • For heat sterilised in final container, consideration given to taking samples from the potentially coolest part of the load

 

ANNEX 2

Manufacture of Biological Medicinal Products for Human Use

• Extraction from biological tissues (such as antivenoms)

Principle

• In process controls take on greater importance in the manufacture of biological medicinal products

Personnel

• Personnel to receive additional training specific to products manufactured
• Personnel given relevant information and training in hygiene and microbiology
• Persons responsible for production and quality control need adequate background in relevant scientific disciplines
• Personnel not to pass from areas where exposure to live organisms is possible to areas where other products are handled

Premises and Equipment

• Where negative pressure areas or safety cabinets are used for aseptic processing of pathogens, they should be surrounded by a positive pressure sterile zone

Animal Quarters and Care

• Animals are used for the manufacture of…snake antivenoms (horses and goats)

Documentation

• Specifications for biological starting materials may need additional documentation on the source, origin, method of manufacture and controls applied, particularly microbiological controls

Production – starting materials

• The source, origin and suitability of starting materials should be clearly defined

ANNEX 8

Sampling of Starting Material and Packaging Materials

• Correct sampling is an essential part of Quality Assurance

Personnel

• Personnel taking samples must receive training in correct sampling techniques

Starting Materials

• The quality of a batch of starting material may be assessed by taking and testing a representative sample.

Packaging Materials

• The sampling plan to take into account: quantity received, quantity required, nature of material, production methods, knowledge of QA systems of the supplier (based on audits)
• Number of samples taken to be determined statistically and specified.

 

ANNEX 9

Manufacture of liquids, creams and ointments

Premises and Equipment

• Use of closed systems recommended
• Tanks, container, pipe work and pumps designed and installed to be readily cleaned and sanitised
• Equipment designed with minimal dead legs or sites where residues can lead to microbial proliferation
• The use of glass apparatus to be avoided wherever possible

 Production

• The microbiological quality of water used in production to be specified and monitored
• Materials likely to shed fibres or other contaminants not to enter areas where products or clean containers are exposed
• Mixing and filling processes to be validated
• Care taken at start, end and after stoppages to ensure homogeneity of product retained
• When finished product not immediately packaged, maximum period pf storage and storage conditions to be specified and adhered to

 

ANNEX 11

Computerised Systems

• Where a computerised system replaces a manual operation, there should be no decreases in quality assurance

Personnel

• Persons in responsible positions to have appropriate training for the management and use of computer systems within their field of responsibility.  Training to include appropriate expertise is available to provide advice on aspects of design, validation, installation and operation of computerised systems

Validation

• The extent of validation depends on whether it is  prospective or retrospective and whether or not novel elements are introduced

System

• A written detailed description of the system must be produced and kept up to date
• The system to include built in checks of the correct entry and processing of data
• Before a computer system is brought into use, through testing and validation is needed and confirmation of the desired operation is required.  If a manual system is being replaced, the two are to be run in parallel for a time as part of the testing and validation
• Data only to be entered or amended by authorised persons.  Procedure to be defined for issue, cancellation and alteration of authorisation to enter and amend data, including the changing of personnel passwords
• When critical data is entered manually, there must be an additional check on the accuracy of the record which is made
• The system to record the identity of operators entering or confirming critical data
• Alterations to a system or to a computer program only to be made in accordance with a defined procedure.  Significant modifications require validation
• It must be possible to obtain meaningful printed copies of data held electronically
• Data to be secured by physical or electronic means against wilful or accidental damage.  Stored data to be checked for accessibility, durability and accuracy
• Data to be protected by regular backups.  Backups to be held at a secure separate location
• Adequate alternative arrangements for systems which need to be operated in the event of a breakdown
• Procedures to be followed if system fails to be defined and validated.  Failures and remedial action to be documented.
• Where using outside agencies to provide a computer service, a formal agreement including a clear statement of the responsibilities of that outside agency is required

 

ANNEX 12

Use of Ionising Radiation In The Manufacture of Medicinal Products

• Two different Gamma irradiation forms: batch mode and continuous

Responsibilities

• Appropriate manufacturing authorisation must exist
• Where process contracted our, pharmaceutical manufacturer bears responsibility for quality of product including the attainment of the objective of irradiation
• The required dose including justified limits will be stated in the marketing authorisation of the product

Dosimetry

• Understanding and correct use of the technique is essential for the validation, commissioning and control of the process
• The calibration of each batch of routine dosimeters should be traceable to a national or international standard.  The period of validity of the calibration should be stated, justified and adhered to

Validation of the Process

• Validation should include dose mapping to establish the distribution of absorbed dose within the irradiation chamber when packed with product in a defined configuration
• An irradiation process specification should include at least the following:
  • Details of packaging of the product
  • The loading pattern(s) of product within the irradiation container
  • The loading pattern of irradiation containers around the source
  • Max and min limits of absorbed dose to the product
  • Irradiation container

Microbiological Monitoring

• Microbiological monitoring is the responsibility of the pharmaceutical manufacture. It may include environmental monitoring where product is manufactured and pre irradiation monitoring of the product as specified in the marketing authorisation

 

ANNEX 15

Qualification and Validation

• Requirements of GMP that manufacturers identify what validation work is needed to prove control of the critical aspects of operations. Significant changes should be validated.  A risk assessment approach should be used to determine the scope and extent of validation

Planning for Validation

• Validation activities should be planned, clearly defined and documented.
• VMP concise and clear
• VMP should contain:

• • Validation policy
  • Organisational structure of validation activities
  • Summary of everything to be validated
  • Planning and scheduling
  • Change control
  • Reference to existing documents

Planning for Validation

• A written protocol established specifying how to conduct validation including critical steps and acceptance criteria.  To be reviewed and approved
• A summary report drawing necessary conclusions required – if validation plan requires changes based ion conclusions, need to be documented and justified
• After completion of a satisfactory qualification, a formal release for the next step in qualification and validation should be made as a written authorisation

Qualification

Design Qualification

• The compliance of the design with GMP should be demonstrated and documented.

Installation Qualification

• Installation qualification (IQ) should be performed on new or modified facilities, system and equipment.

Operational Qualification

• Operational qualification (OQ) should follow IQ

Performance Qualification

• Performance qualification (PQ) should follow the successful completion of IQ and OQ.

Qualification of established (in-use) facilities, systems and equipment

• Evidence should be available to support the operating parameters and limits, cleaning, preventative maintenance, operating procedures and operator training procedures and records should be documented.

Process Validation

• Process validation should be completed prior to the distubution and sale of the medicinal product.  Processes in use should also be validated (retrospective validation)
• Facilities, systems and equipment should be qualified and analytical testing methods should be validated.  Staff taking part in the validation work should have been appropriately trained.
• Facilities, systems and equipment should be periodically evaluated to verify that they are still operating in a valid manner

Prospective validation

• Validation should include:
  • Process description
  • Summary of steps to investigate
  • List of all materials to be used, as well as the calibration status of equipment
  • Finished product specifications
  • List of methods as appropriate
  • Proposed in process controls with acceptance criteria
  • Additional testing with acceptance criteria and analytical  validation as appropriate
  • Sampling plan
  • Methods for recording and evaluating results
  • Functions and responsibilities
  • proposed timetable
• The number of process runs carried out and observations made should be sufficient to allow for normal variation and trends to be established.  Generally accepted that x3 consecutive batches/runs within agreed parameters would constitute a process validation
• Batches made for process validation should be same size as commercial batches
• If validation batches intended to be sold, manufacturing conditions ro fully comply with GMP

Concurrent Validation

• The decision to carry our concurrent validation must be justified, documented and approved by authorised personnel

Retrospective Validation

• Retrospective validation is only acceptable for well-established processes and will be inappropriate where there have been recent changes in the composition of the product, operating procedure or equipment.
• Batches selected for retrospective validation should be representative of all batches made including batches that failed to meet specifications
• For retrospective validation, generally data from ten to thirty consecutive batches should be examined to assess consistency.

Cleaning Validation

• Cleaning validation should be performed in order to confirm the effectiveness of a cleaning process.  The limits should be achievable and verifiable.
• Validated analytical methods having sensitivity to detect residues or contaminants should be used.
• Only cleaning procedures for product contact surfaces of the equipment need to be validated  the intervals between cleaning and use as well as cleaning and reuse should be validated.
• For products and processes which are similar, acceptable to select a representative range of similar products and processes.  A single validation study utilising ‘worst case’ approach can be carried out which takes into account the critical issues
• Three consecutive applications of the cleaning procedure should be performed an d shown to be successful

Change Control

• Written procedures to describe the actions to be taken if a change is proposed

• Changes that may affect product quality or reproducibility of the process should be formally requested, documented and accepted

Revalidation

• Facilities, systems, equipment and processes, including cleaning, should be periodically evaluated to confirm that they remain valid. Where no significant changes have been made to the validated status, a review with evidence that facilities, systems, equipment and processes meet the prescribed requirements fulfils the need for revalidation.

 

ANNEX 17

Parametric Release

• Definition of parametric release “A system of release that gives the assurance that the product is of the intended quality based on information collected during manufacturing processes and on the compliance with specific GMP requirements related to Parametric Release”

Parametric Release for sterile products

• Parametric release can only be approved for products terminally sterilized in their final container.

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