TGA - GMP Audit Checklist
TGA - GMP Audit Checklist
TGA - GMP Audit Checklist
Company Name
This form is intended for internal use by Manufacturers and will not normally be used by APVMA-Authorised
Auditors during GMP audits.
This checklist lists the major points which will be addressed by the GMP auditors when auditing a manufacturing
premises against the Australian Code of Good Manufacturing Practice for Veterinary Chemical Products, 2007
(and relevant annexes). Attention to the matters on this checklist will assist manufacturers to meet their obligations
in upcoming GMP audits.
Each item in the checklist should be assessed for level of compliance with the GMP Code, using the following
criteria:
Acceptable - satisfactory or substantial compliance with the GMP Code;
Minor non-conformance – minor or less serious non-conformance which may not pose a risk to product quality;
Major non-conformance – failure to satisfy a key or mandatory requirement and/or one which may pose a risk to
product quality;
Critical non-conformance – a major non-conformance which poses a risk to treated animals or users and must be
corrected immediately (indicate with a “C” in the major non-conformance column).
Manufacturing principles
Manufacturers of veterinary chemical products must have in place a quality assurance system to ensure that finished products are fit for their intended use, comply with
registration requirements and do not place treated animals or users at risk due to inadequate quality, safety or efficacy.
The quality assurance system must be relevant to the nature and intended use of the product. It must be fully documented, monitored for effectiveness and provide for
continuous improvement.
Management of quality
Check Checkpoint Acceptable Minor Major Not
Point non non Audited
No. conformance conformance
101 Documented quality assurance system, supported by management, in place. Quality requirements are understood,
implemented and maintained at all levels of the organisation. Adequate resources provided to achieve this.
102 A senior manager has responsibility for the overall direction and management of quality within the organisation.
103 Management reviews the quality assurance system at stated, regular intervals (no greater than every three years), to
ensure the continued suitability, adequacy and effectiveness of the system, and its continual improvement. That
review evaluates any changes to the quality system that have taken place. Management review process documented
and records of the review maintained.
Quality assurance
104 The quality assurance system ensures that:
(a) managerial responsibilities are clearly defined, documented and exercised;
Quality control
105 A system of quality control is in place to ensure that products comply with their required specifications and standards,
as described in Chapter 8 of the GMP Code.
Key observations and comments (Comment on both positive and negative aspects of Quality Management. Record evidence sighted and reviewed, such as policy
documents, records, etc, particularly with respect to non-conformance) .
Manufacturing principles
Veterinary chemical products must be manufactured under the management and supervision of appropriately qualified, trained or experienced persons who:
understand the specialised technical, quality and legal requirements relating to the manufacture of veterinary chemical products for which they have responsibility
have their duties and responsibilities clearly defined by the manufacturer.
General
Check Checkpoint Acceptable Minor Major Not
Point non non Audited
No. conformance conformance
201 The manufacturer has an adequate number of personnel with the necessary qualifications, training or practical
experience. The responsibilities placed on any one individual are not so extensive as to present a risk to quality.
202 The manufacturer has an organisational chart showing the names of key personnel, as well as their areas of
responsibility and lines of authority.
203 People in responsible positions have written job descriptions describing their specific duties. There are no gaps or
unexplained overlaps in the responsibilities of those personnel concerned with the application of GMP.
204 People in responsible positions have adequate authority to carry out their responsibilities.
205 Where the duties of persons in responsible positions are delegated to designated deputies with relevant qualifications
and experience, records are kept of those delegations.
206 Operators’ verbal and written communication skills are sufficient for them to respond to training, accept and
implement instructions exactly and, where their duties require it, fill out forms correctly.
Key personnel
Check Checkpoint Acceptable Minor Major Not
Point non non Audited
No. conformance conformance
207 Key personnel include the persons nominated as responsible for Production and for Quality and, if neither of these
persons is responsible for product release, the person(s) authorised for that purpose. Key positions are occupied by
full-time personnel.
208 The persons responsible for Production and for Quality are independent from each other. In small operations where
this may not be possible, the quality control function and procedures are clearly documented and shown to be
effective.
209 The person with overall responsibility for Production has responsibility to:
(a) ensure that products are produced and stored according to documented procedures
(b) approve procedures relating to production operations and ensure their strict implementation
(c) approve and monitor any subcontracted production work
(d) ensure that production records are evaluated and signed by an authorised person before they are submitted for
product release
(e) ensure that production areas, premises and equipment are maintained to an appropriate standard
(f) ensure that appropriate validations are conducted
(g) ensure that initial and continuing training of production personnel are conducted, according to need.
210 The person with overall responsibility for Quality has responsibility to:
(a) evaluate and authorise master manufacturing and packaging documents
(b) approve specifications, sampling instructions, test methods and other quality control procedures
(c) approve or reject raw materials, packaging materials, and intermediate, bulk and finished products
(d) review completed batch records as part of the release procedures
(e) ensure that all necessary testing is carried out
(f) approve and monitor any contract analysts
(g) monitor quality performance of subcontract manufacturers
(h) check the maintenance of the quality control area, premises and equipment
(i) ensure that appropriate validations are conducted
Key observations and comments (Comment on both positive and negative aspects of Personnel and Training. Record evidence sighted and reviewed, such as policy
documents, SOPs and records, particularly with respect to non-conformance) .
Manufacturing principles
Veterinary chemical products must be manufactured in buildings that are located, designed, constructed, maintained and utilised to:
suit the operations carried out in them
ensure protection of the veterinary chemical products from contamination
permit effective cleaning and maintenance, including cleaning after processes have been completed
minimise the risk of manufacturing error.
The products must also be manufactured in an environment, or in equipment fitted with precautionary measures, that:
ensures a standard of hygiene appropriate to the class of veterinary chemical product being manufactured
minimises the risk of cross-contamination of the finished product, or of materials or components that are used or manufactured at the premises
ensures the safety of operators and protects the outside environment.
General
Check Checkpoint Acceptable Minor Major Not
Point non non Audited
No. conformance conformance
301 Premises are situated in an environment that presents minimal risk of causing contamination of materials or products.
(For example, locations in close proximity to chemical works or trades likely to result in pollution or contamination of
product are avoided unless special precautions are taken).
302 The premises, including the surrounding grounds and gardens, are kept in an orderly, neat and tidy condition.
303 Premises are designed, constructed and maintained to minimise the effects of weather and ground seepage, the entry
and accumulation of dust and other airborne materials, and the entry of insects, birds, rodents, vermin and other
animals. Cavities and voids are minimised and, where necessary, provided with access for pest control purposes.
304 Each part of the premises is suitable for the operations being carried out and kept in good repair. Repair and
maintenance operations do not present any hazard to product quality.
305 Lighting, temperature, humidity and ventilation are appropriate for the type of operations being undertaken. They do
not directly or indirectly, adversely affect product quality during manufacture and storage, or the accurate functioning
of equipment. Air intakes are located away from sources of contamination.
306 Sinks are made of stainless steel, without overflow and preferably spaced 50 mm away from walls so as to avoid
uncleanable joins and crevices. Where appropriate, they have effective, easily cleanable traps and air breaks to
prevent backflow.
Production areas
Check Checkpoint Acceptable Minor Major Not
Point non non Audited
No. conformance conformance
325 The operations carried out in any particular area are compatible, so that the integrity of any product made in the area is
not threatened.
326 Manufacture of sterile, highly active, toxic or infective products is normally performed in dedicated, self-contained
facilities. Processes that may give rise to significant risk from cross-contamination also require such facilities. (Note
that campaign manufacture in the same facilities may be accepted, provided that specific, documented precautions
are taken).
327 Registered veterinary medicinal products are not manufactured in the same areas as poisonous, toxic or hazardous
unregistered consumer products.
328 Veterinary chemical products containing technical poisons are handled in segregated areas or separate buildings,
usually with equipment dedicated to this class of product. (However, common areas or equipment may be accepted,
provided that cross-contamination is controlled by scheduling or use of a validated cleaning procedure).
329 Premises are laid out in a way that allows the orderly and logical positioning of equipment and materials so as to
minimise the risk of confusion between different veterinary chemical products or their components, to avoid cross-
contamination and to minimise the risk of omission or wrong application of any of the manufacturing or control steps.
330 Where starting and primary packaging materials, or intermediate or bulk products are exposed to the environment,
interior surfaces (walls, floors and ceilings) are suitable for the class of product being manufactured. (This will
usually require surfaces that are nonporous, smooth, free from open joints, and do not shed particulate matter).
Interior surfaces permit effective cleaning.
331 Joins between walls and floors are easy to clean, adequately sealed and where appropriate, coved to form a smooth
curve between the floor and wall.
332 Wood or wood-based materials are avoided as a material of construction or support for equipment or materials in
production areas, especially where they may be wetted. If used, they are sealed with a coating that is resistant to
chipping, disinfectants and cleaning agents and that is easily cleaned.
333 The use of wood-based pallets is avoided in production areas where there is a risk of contamination of the product.
334 Pipe work, light fittings, ventilation points and other services are designed and located to avoid the creation of recesses
that are difficult to clean. As far as practicable, they are accessible from outside the manufacturing areas for
maintenance purposes.
335 Production areas are effectively ventilated and allow, where necessary, control of air flow, temperature, humidity and
filtration appropriate to the products handled, the operation undertaken and the external environment.
Ancillary areas
343 Staff amenities, including lunch rooms, are separate from storage, production and quality control areas.
344 Clean and well-ventilated toilets and changing rooms are provided. These are easily accessible and suitably isolated
from any production, quality control or storage areas. They are appropriate for the number of users and are maintained
in a tidy and hygienic manner, with an adequate supply of hot and cold water, soap and hygienic hand-drying
facilities.
345 A sufficient number of clean hand basins, with a satisfactory supply of hot and cold water, soap or detergent
dispensers, and hygienic hand-drying facilities are provided near working areas for use by production personnel.
346 Maintenance workshops should, as far as possible, be separate from production areas. Whenever parts or tools are
stored in the production area, they are kept in rooms or lockers reserved for that use.
Animal houses
Check Checkpoint Acceptable Minor Major Not
Point non non Audited
No. conformance conformance
347 Areas in which animals are housed are adequately isolated from storage and processing areas, with separate access for
animals and separate air handling facilities.
Key observations and comments (Comment on both positive and negative aspects of Buildings and Grounds. Record evidence sighted and reviewed, such as SOPs,
records and observations, particularly with respect to non-conformance) .
Manufacturing principles
Equipment used in the manufacture of veterinary chemical products must be suitable for its intended purpose and appropriately operated, maintained and cleaned. Equipment
must be correctly installed and operated in accordance with written instructions that are appropriate for the equipment.
General
Check Checkpoint Acceptable Minor Major Not
Point non non Audited
No. conformance conformance
401 Equipment used for the manufacture (including testing) of veterinary chemical products, is designed, located and maintained to suit
its intended purpose and installed and positioned in such a way as to minimise any risk of error or cross-contamination.
402 Equipment is used in accordance with written instructions that are appropriate to the equipment and consistent with any operating
instructions issued by the equipment manufacturer.
403 Production equipment does not present any hazard to the manufactured products (eg by contamination of processed materials or
finished products, or their containers, with lubricants or other extraneous substances). The parts of the production equipment that
come into contact with materials being processed or the finished product are not reactive, additive, or absorptive to such an extent
that product quality is adversely affected.
404 Equipment is uniquely identified. This identification is traceable to all records pertaining to the equipment.
405 If prone to failure or variance, equipment used for critical steps in the manufacturing process is monitored by devices capable of
recording the necessary operating parameters, or is equipped with alarm devices to indicate malfunction. If such devices are not
practical, the output is monitored to ensure early detection of variance.
406 Balances and other measuring equipment required for production and quality control operations are available and have an
appropriate range and degree of precision. Equipment is properly positioned before use.
407 Fixed pipe-work is clearly labelled to indicate the contents and, where applicable, the direction of flow. Pipes are adequately sloped
for drainage and constructed without ‘dead-legs’. There are measures in place to ensure that materials transferred via pipelines are
delivered to the correct destination.
408 Defective equipment is, where possible, removed from production and quality control areas. If it cannot be removed, it is clearly
labelled as defective.
Maintenance
411 All equipment is properly maintained and records of this maintenance are kept. In addition, equipment is inspected for
serviceability before any operation begins.
412 Repair and maintenance operations do not present any hazard to product quality.
413 Where continued maintenance of specific equipment is essential to product quality, documented maintenance
procedures and records include the following:
(a) details and frequency of preventive maintenance requirements;
(b) action to be taken if equipment maintenance requirements cannot be met;
(c) records of preventive maintenance, including the name of the service-person , any deviation from the procedure
and a statement or authorising signature documenting the condition of the equipment following the service.
Calibration
414 Each item of equipment used in manufacture or for quality control purposes that measures, or depends on, a physical
parameter (eg measuring, weighing, recording and control equipment), is calibrated at defined intervals, in accordance
with a written procedure. That procedure describes the method and frequency of calibration or observation, taking
into account any statutory requirements, as well as the action to be taken when results deviate from defined acceptance
limits.
415 Where appropriate, verification checks are performed at a frequency consistent with the use of the equipment, in
accordance with a written procedure.
416 Records are kept of any calibrations, verification checks or observations carried out on such equipment. Those records
contain sufficient information to show that the required calibrations/observations have been carried out and provide
details of any necessary corrective action taken.
Calibration (cont)
Check Checkpoint Acceptable Minor Major Not
Point non non Audited
No. conformance conformance
417 Equipment calibration records show the actual results observed and the acceptance criteria.
418 Where practicable, each item requiring calibration bears a label or tag indicating that calibration has been carried out
and when the next calibration is due. (Alternatively, a computer-based maintenance system that flags the need for
calibration can be accepted, provided that it can be shown to be working effectively).
419 There is evidence to demonstrate that the particular calibrating devices used are themselves accurate. Contractors who
calibrate equipment are certified by a certification agency.
Cleaning
420 Manufacturing equipment is designed so that it can be easily and thoroughly cleaned. Where necessary, it is easily
dismantled for cleaning. It is cleaned according to detailed written procedures, and stored only in a clean, dry
environment. Records are kept of equipment cleaning operations.
421 To facilitate cleaning, equipment is mobile or clear of walls and floors. Where this is not practical, equipment is
sealed to the surfaces it touches.
422 Permanently fixed product and process-water pipelines have sanitary couplings and are sloped for drainage.
423 Washing and cleaning equipment is chosen and used in such a way that it is not a source of contamination.
424 Pipes for distilled, purified and, where appropriate, other water are sanitised according to written procedures that
describe the action limits for microbiological contamination and the measures to be taken if action limits are exceeded.
425 Equipment is cleaned to the frequency and extent necessary to preserve product integrity. A cleaning record is kept
either on the batch record or in an equipment log book.
426 Validation of cleaning procedures is considered where traces of ingredient may pose significant risk of contamination
or toxicity in following product batches.
Key observations and comments (Comment on both positive and negative aspects of Equipment. Record evidence sighted and reviewed, such as SOPs, records and
observations, particularly with respect to non-conformance).
Manufacturing principles
Manufacturers of veterinary chemical products must establish and maintain a system of documentation, document control and record keeping that:
provides precise specifications for starting materials, intermediate materials and finished products, manufacturing formulae and instructions and operating procedures for
associated manufacturing and quality control activities
provides a complete history of each item, batch, or quantity manufactured in a specified timeframe, of veterinary chemical product produced at the premises
establishes a traceable connection between raw materials and the finished product.
General
Check Checkpoint Acceptable Minor Major Not
Point non non Audited
No. conformance conformance
501 All processes and associated activities in the manufacture of veterinary chemical products are documented and the
documents subjected to a system of document control.
502 Manufacturing documentation is designed, prepared, reviewed and distributed with care. It complies with the relevant
parts of product registration dossiers and registered particulars for the product and is regularly reviewed and kept up to
date.
503 Documents are approved, signed and dated by appropriate and authorised persons. In the case of master
manufacturing formulae, manufacturing instructions, and packaging and labelling instructions, a second authorised
person checks, reconciles, endorses and dates both the formula and instructions.
504 The issue of working documents and forms is limited to photocopying from current, authorised, signed, hard master
documents or printing from access-controlled authorised electronic versions.
505 Documents are legible, readily identifiable and retrievable. They do not include superfluous data and, at the working
level, are written in the imperative (ie as instructions rather than statements of what is desired). They are laid out in an
orderly fashion and are easy to check.
506 Documents are not handwritten. Where data entries are handwritten or machine-printed, they are clear, legible and
permanent. Sufficient space is provided for such entries.
507 The contents of documents are unambiguous. The title, nature and purpose are clearly stated. The document clearly
identifies the way in which it is to be used, and by whom it is to be used. It includes, or is identifiable to, the issuing
premise and also includes the following information:
(a) a unique number identifying the document;
Document control
512 The system of document control is documented. That document definesw the procedures in place for:
(a) approval and regular review of documented procedures;
(b) distribution of documents;
(c) removal of obsolete documents from all points of issue and use;
(d) prevention of inadvertent use of superseded documents.
513 A documented procedure is in place that defines the controls needed for the storage, protection, retrieval, retention
time and disposal of records.
514 The system of document control includes a list of all controlled documents and identifies the current revision status of
any controlled document and the holder/location of that document.
515 Changes to controlled documents are acted upon promptly. They are reviewed, dated and signed by the authorised
person(s) and formally implemented. There are records to show that all relevant personnel have acknowledged
subsequent changes to procedures.
Records
517 Records are made or completed at the time each action is taken.
518 Manufacturing records are retained by the manufacturer for the period specified in the Agricultural and Veterinary
Chemicals Code Regulations 1995, as cited below.
519 Data may be recorded by electronic data processing systems, photographic or other reliable means, but detailed
procedures relating to the system in use are available and the accuracy of the records are checked.
520 If documentation is handled by electronic data processing methods, only authorised persons are able to enter or modify
data in the computer and there is a record of changes and deletions. Access is restricted by passwords or other means.
See Chapter 6 (Computer Systems) of the GMP Code for details.
521 Batch records that are stored electronically are backed up by suitable means on a regular basis. Data are readily
available throughout the period of retention.
522 Consideration is given to storage of batch records and other critical records in a safe and secure environment.
Regulation 61(5) A holder of a licence must keep at the premises to which the licence relates:
(a) the records in subregulation (3); and
(b) if it is not unreasonable in the circumstances – a sample from each batch of the finished products;
for at least 12 months after the expiry date of the products to which they relate or, if there is no expiry date, for at least 6 years after the date on which the manufacture of the
products was completed.
Documents required:
Specifications
Check Checkpoint Acceptable Minor Major Not
Point non non Audited
No. conformance conformance
523 There are authorised and dated specifications for starting and packaging materials, as well as finished products,
appropriate for the type of product being made and consistent with data submitted for product registration. Where
appropriate, they are also available for intermediate or bulk products.
524 Specifications for starting and primary or printed packaging materials include, where applicable:
(a) a description of the materials, including:
(i) the designated name and the internal code reference;
(ii) reference, if any, to a pharmacopoeial monograph, or any other document on which the specification is
based;
(iii) the approved source of any active material;
(iv) the preferred suppliers; and, if relevant, the original producer of the materials;
(v) a specimen of printed materials;
(b) directions for sampling and testing, or reference to procedures;
(c) qualitative and quantitative requirements with acceptance limits;
(d) storage conditions and precautions;
(e) the maximum period of storage before re-examination;
(f) any relevant safe handling instructions.
525 Where specifications for raw materials are based on a valid certificate of analysis provided by a supplier, a copy of
that certificate of analysis is suitably identified and authorised by an appropriate person and retained as part of the
manufacturer’s specifications.
526 Specifications for intermediate and bulk products are available if these are purchased or despatched, or if data obtained
from intermediate products are used for the evaluation of the finished product. The specifications are similar to
specifications for raw materials or for finished products, as appropriate.
Specifications (cont)
Check Checkpoint Acceptable Minor Major Not
Point non non Audited
No. conformance conformance
527 Specifications for finished products include:
(a) the designated name of the product and the code reference where applicable;
(b) a description of the pharmaceutical form and package details;
(c) the qualitative and quantitative requirements, such as visual, organoleptic, physical, chemical and
microbiological, with the acceptance limits;
(d) the storage conditions, shelf life and any special handling precautions, where applicable.
Master manufacturing formula, master batch records and master manufacturing processing instructions
533 Formally authorised master manufacturing formula and master manufacturing (or processing) instructions, that are
appropriate for the type of product being made and consistent with data submitted for product registration, exist for
each product and batch size to be manufactured. They may be combined in one document.
534 The master manufacturing formula and master manufacturing instructions are prepared, endorsed and dated by a
competent person delegated by management. A second authorised person checks, endorses and dates the instructions
where possible. They are kept up to date at all times and reviewed at specified intervals not exceeding three years.
Any amendments are checked by a second competent person.
535 The master manufacturing formula/master batch records include:
(a) the name of the product, with a product reference code relating to its specification;
(b) a description of the pharmaceutical form (eg liquid, powder, cream), strength or potency of the product, and
batch size;
(c) a list of all raw materials to be used, with the amount of each (quantity per unit dose and the quantity per batch),
using the designated name and provision for entry of the manufacturer’s UIN;
(d) a statement of the percentage excess, where a predetermined excess (overage) of any ingredient is used;
Master manufacturing formula, master batch records and master manufacturing processing instructions (cont)
Check Checkpoint Acceptable Minor Major Not
Point non non Audited
No. conformance conformance
(e) provision for making any adjustments for potency, moisture etc; mention are made of any substance that may
disappear in the course of processing;
(f) provision for entry of the expected final yield, with the acceptable limits and of relevant intermediate yields,
where applicable.
Where practicable, batch sizes are standardised.
536 The master manufacturing (or processing) instructions include:
(a) a statement of the processing location and the principal equipment to be used;
(b) the methods, or reference to the methods, to be used for preparing the critical equipment (eg cleaning,
assembling, calibrating, sterilising);
(c) detailed stepwise processing instructions (eg checks on materials, pre-treatments, sequence for adding materials,
mixing times, temperatures) with provision to record relevant data, such as time, pH, temperature;
(d) the instructions for any in-process controls, with their limits;
(e) where necessary, the requirements for bulk storage of the products, including the container, labelling and special
storage conditions and/or time limits, where applicable;
(f) any special precautions to be observed with regard to product quality and personal safety (eg scheduling to
prevent cross-contamination, clothing requirements, directions for dealing with spills, if relevant);
(g) provision for operator initials or signatures at suitable stages;
(h) a summary of all necessary quality control tests and analyses, and at what stage they are to be carried out.
Computer records
551 Where computer systems are used to store critical manufacturing information or control manufacturing processes,
records are maintained as required by Chapter 6 of the GMP Code.
Laboratory records
552 Records maintained in quality control laboratories meet the requirements of Chapter 8 of the GMP Code.
Validation records
553 Records are kept of all validation studies carried out. In addition to the raw data, the records include a technical
report, set out in report format, providing details of the rationale for the study, the methods used, when and by whom it
was carried out, the results and the conclusions.
Other records
Check Checkpoint Acceptable Minor Major Not
Point non non Audited
No. conformance conformance
554 There are written procedures and records of actions taken or conclusions reached, where appropriate, for:
(a) pest control (including details of any pest control program implemented, records of observations made as part of
that program and any casual sightings, and details of any corrective action taken);
(b) general maintenance, cleaning and sanitisation (cleaning and sanitising instructions should include the name and
strength of any cleaning/sanitising agent used);
(c) equipment installation and assembly, qualification and calibration (qualification and calibration records should
show tolerance limits);
(d) equipment maintenance, cleaning and sanitisation (cleaning and sanitising instructions should include the name
and strength of any cleaning/sanitising agent used);
(e) personnel matters, including medical checks, training, clothing and hygiene;
(f) environmental monitoring (including temperature and other controlled-environment monitoring devices).
555 Clear operating procedures and, where appropriate, specific cleaning instructions, are available for major items of
manufacturing and test equipment.
556 Log books or equivalent records are kept for major or critical equipment, to record any validations, calibrations,
maintenance, or repair operations, including dates and the identity of people who carried out those operations.
557 Log books or equivalent records also record, in chronological order, the use and cleaning of major or critical
equipment and of the areas where the products have been processed.
Key observations and comments (Comment on both positive and negative aspects of Documentation and Records. Record evidence sighted and reviewed, such as
SOPs and records, particularly with respect to non-conformance).
Manufacturing principles
Where, in any step of manufacture, a computer is used for any activity that may affect the quality, safety or efficacy of a product, then the computer system must be subject to
quality system management principles to ensure operational suitability.
The introduction of computer systems into any manufacturing process, including materials control, processing control, quality control and product distribution, must not
adversely affect product quality or quality assurance.
General
Check Checkpoint Acceptable Minor Major Not
Point non non Audited
No. conformance conformance
601 A written description of the system is available and kept up to date. It describes the objectives of the system and how
it interfaces with other systems and processes.
602 Before a system involving a computer is brought into use, it is thoroughly tested and shown to be capable of achieving
the intended outcomes. If a manual system is being replaced by a computer system, or the computer system is being
upgraded, both systems are run in parallel for a time as part of this testing and validation. The extent of validation
necessary will depend on a number of factors, including the intended outcomes, whether it is prospective or
retrospective and whether novel elements are incorporated.
603 If software has been commissioned specifically for the manufacturer, its development is documented at all stages and
each step evaluated by expert review against the written objectives. The stages to be documented include planning,
specification, programming, testing, installation and operational performance qualification.
604 If the software is ‘off-the-shelf’, but has been configured for the manufacturer’s use, then installation qualification and
operational qualification are undertaken. This includes a list of the values/fields/variables/parameters that have been
chosen, with detail of how this information is secured and made subject to change control and details of the tests for
security that were applied. The operational qualification shows how the system successfully handles instructions and
data.
605 If ‘off the shelf’ software has been partly or fully customised, its development is treated as in 603 above.
606 If the software is ‘off-the-shelf’ and has not been configured or customised for use, then it is precisely defined and
installation and performance qualification are carried out to demonstrate that user requirements have been satisfied.
Key observations and comments (Comment on both positive and negative aspects of Computer Systems. Record evidence sighted and reviewed, such as SOPs and
records, particularly with respect to non-conformance) .
Manufacturing principles
Veterinary chemical products must be manufactured to specifications in accordance with manufacturing information supplied as part of their application for registration and/or
any subsequent approved variations.
Production operations must follow documented procedures that have been clearly defined by the manufacturer.
Any critical manufacturing process and any change to that manufacturing process, must be validated and formally approved by an authorised person. Where a change in the
manufacturing process affects the registered specifications of the finished product, formal approval of such changes must be obtained from the registering authority before the
affected product is released for supply.
General
Check Checkpoint Acceptable Minor Major Not
Point non non Audited
No. conformance conformance
701 Each material used is consistent with documented specifications and the master manufacturing formula, and each step
of manufacture carried out (such as receipt and quarantine, quality assurance of raw materials, dispensing, processing,
packaging, labelling and quality control procedures) is in accordance with documented procedures and the master
manufacturing instructions.
702 For each batch of product made, records are kept of all materials used and of all critical steps and control procedures
carried out.
703 All surfaces which come into contact with raw materials, intermediate materials and finished product are maintained at
an appropriate level of cleanliness at all stages of manufacture.
704 The manufacturing process are periodically monitored at all critical stages to ensure both the reliability of the
manufacturing process and product quality, including microbial testing if relevant.
705 The identity and where relevant, the status of every material, including waste, is clearly shown on the outside of its
container.
Cross-contamination control
724 Cross-contamination is minimised by appropriate technical or organisational measures, which may include:
(a) production in physically segregated areas (required for products such as live vaccines, live bacterial
preparations and some other biologicals, as well as penicillins and other highly sensitising materials);
Process validation
726 Critical steps in the manufacture of each product or product group are validated with supporting data. The extent and
method of validation/revalidation are appropriate for the manufacturing method and the type of product and its use.
727 When any new manufacturing formula, method of preparation or significant change is adopted, steps are taken to
demonstrate its suitability for routine processing. The defined process, using the materials and equipment specified, is
shown to yield a product consistently of the required quality.
728 Validation studies are conducted in accordance with defined procedures. They include the most challenging of any
permitted ranges in process variables. Results and conclusions are recorded as technical reports.
Production procedure
(a) Dispensing of raw materials
729 The raw materials used for a particular product conform to the master manufacturing formula. No substitution is
allowed unless the change is authorised in writing by an authorised person.
730 Only raw materials that have been released for use and which are within their shelf life, are used.
Key observations and comments (Comment on both positive and negative aspects of Production Procedures. Record evidence sighted and reviewed, such as SOPs,
records and observations, particularly with respect to non-conformance) .
Manufacturing principles
Manufacturers of veterinary chemical products must have in place an effective quality control system which is designed to ensure that, before products are released from
manufacture for supply, they meet specifications and have been manufactured in accordance with the manufacturer’s documented procedures.
The person responsible for quality control must be sufficiently independent of other aspects of the manufacturing operation to allow effective implementation of the quality
control function.
Manufacturers must ensure that analytical laboratories and animal testing facilities used in a step of manufacture follow the principles of good laboratory practice.
General
Check Checkpoint Acceptable Minor Major Not
Point non non Audited
No. conformance conformance
801 The manufacturer has an identifiable quality control function. This function is independent from other functions and
under the authority of a person (with appropriate qualifications and experience), who has access to one or more control
laboratories. Adequate resources are available to ensure that all the quality control arrangements are effectively and
reliably carried out.
802 Where practicable, a quality control laboratory is available and adequately staffed and equipped for the performance of
all quality control tests required before, during and after manufacture. Where there is no in-house facility, or the in-
house facility does not have the capability of doing all required quality tests, satisfactory alternative arrangements for
the required quality control testing exist.
803 The principal duties of the head of Quality Control are summarised in Chapter 2 (clause 210) of the GMP Code.
Quality Control also has other duties, which may include:
(a) establishing adequate quality control specifications for all materials at all stages of manufacture and for the
finished product;
(b) establishing, documenting, validating and implementing all quality control test procedures;
(c) assessing and releasing/rejecting starting and intermediate materials for each batch;
(d) assessing and releasing/rejecting each batch of finished product for supply;
(e) keeping reference/retention samples of materials and products;
(f) ensuring the correct labelling of containers of materials and products;
Documentation
809 Laboratory documentation follows the general principles given in Chapter 5 ‘Documentation’ of the GMP Code. The
following information is either prepared by, or readily available to, Quality Control:
(a) specifications;
(b) sampling procedures;
(c) testing procedures and records (including analytical worksheets and/or laboratory notebooks);
(d) analytical reports and/or certificates;
(e) data from environmental monitoring, where required;
(f) validation records of test methods, where applicable;
(g) procedures for and records of, the calibration of instruments and maintenance of equipment.
810 Any quality control documentation relating to a batch record is retained for the period defined in clauses 517-522, in
Chapter 5 of the GMP Code.
811 Records of analytical test results, yields and environmental controls are kept in a manner permitting trend evaluation.
812 In addition to the information that is part of the batch record, other original data such as laboratory notebooks and/or
records are retained and readily available.
Sampling
(a) Sampling plans
813 Sampling plans for starting materials (excluding packaging materials):
(a)* differentiate between certified, approved and other suppliers, including unknown suppliers, as appropriate;
Product release
824 Products are released in accordance with the procedures specified in Chapter 5 in the GMP Code.
Key observations and comments (Comment on both positive and negative aspects of Quality Control. Record evidence sighted and reviewed, such as SOPs and
records, observations, etc, particularly with respect to non-conformance) .
Manufacturing principles
Where all or part of the manufacture of a veterinary chemical product is contracted to another party, the licensed manufacturer(s) must ensure that, before manufacture
commences, both parties have signed a written ‘GMP Agreement’ that clearly specifies each party’s responsibility in relation to every aspect of the manufacturing process,
assurance of product quality and consistency with product registration particulars.
Arrangements for contracted steps of manufacture must not compromise the quality of the product.
Where a contractor is authorised to manufacture under the licence of another manufacturer, the licence holder must exert direct control and oversight of the quality
management of the contracted step.
General
Check Checkpoint Acceptable Minor Major Not
Point non non Audited
No. conformance conformance
901 Contracted manufacture may involve the entire production and packaging processes, or steps such as tablet coating,
packaging, labelling, sterilisation, analysis or testing and release for supply.
902 When the manufacturer (‘contract giver’) contracts all or some of the steps of manufacture to another manufacturer
(‘contract acceptor’), a written agreement (usually referred to as a ‘GMP Agreement’ or ‘Specification of GMP
Responsibilities’) is drawn up that clearly defines the steps of manufacture, or scope of any analytical work, to be
carried out. It also defines the GMP responsibilities of each party for each aspect of the work. All GMP Agreements
are kept up to date.
903 Contract manufacture is undertaken only by a manufacturer who is the holder of an APVMA Manufacturer’s Licence,
unless the work undertaken by the contract acceptor falls within the scope of the contract giver’s licence as specified
in Agricultural and Veterinary Chemicals Code Regulations 1995, cited below.
Regulation 59A: A person who performs only a single step in the manufacture of a product is an exempt person in relation to the manufacture if:
(a) the step consists only of:
(i) packaging or labelling, or both packaging and labelling, the product; or
(ii) analysing or testing the product; and
(b) either:
(i) the licence that authorises the manufacture of the product (being a licence held by another person) permits the first-mentioned person to perform the step for the product; or
(ii) the step consists only of applying a label that contains only a name and address, or the registration number of the product, or both, to a package, or packages of the product.
Key observations and comments (Comment on both positive and negative aspects of Contract Manufacture. Record evidence sighted and reviewed, such as SOPs.
GMP contracts and records, particularly with respect to non-conformance).
Manufacturing principle
Manufacturers of veterinary chemical products must regularly and systematically carry out internal audits of all aspects of their manufacturing operations, as well as of
their quality assurance program, in order to monitor compliance with their authorised procedures, standards and requirements and ensure product quality. Steps must be
taken to implement any necessary corrective and preventive action identified by those internal audits and to assess the outcomes.
General
Check Checkpoint Acceptable Minor Major Not
Point non non Audited
No. conformance conformance
1001 A program of planned and documented internal audits (self-inspections) is in place to regularly and systematically
assess all aspects of manufacture and quality control for compliance with GMP and to assess the effectiveness of the
quality assurance system. Those audits cover all aspects of manufacture. The frequency and scope of audits takes into
consideration the status and importance of the areas to be inspected, as well as the results of previous audits.
1002 Internal audits are conducted by staff who have been trained and are competent in internal audit procedures, and where
practicable, staff who do not have direct responsibility for the processes being audited. Alternatively, independent
external auditors are used.
1003 Where the need for corrective action has been identified, steps are taken to address any observed deviations from the
documented quality system and manufacturing procedures. Corrective and preventive actions are monitored for
effectiveness and modified if necessary. Documented procedures are amended if there is an identified need to do so.
1004 Records are kept of all internal audits undertaken, the outcomes of those audits, details of any corrective and
preventive action taken and the effectiveness of such action.
Key observations and comments (Comment on both positive and negative aspects of Contract Manufacture. Record evidence sighted and reviewed, such as SOPs
and records, particularly with respect to non-conformance) .
Manufacturing principles
Manufacturers of veterinary chemical products must have in place a system of handling complaints regarding products they have manufactured or otherwise handled on the
licensed premises. There must be a documented system of recording, investigating and, where appropriate, acting upon all complaints that may be related to product quality.
Manufacturers must also have in place a documented and effective procedure for recalling from the marketplace product that is known to be defective, or is suspected of being
defective.
Complaints
Check Checkpoint Acceptable Minor Major Not
Point non non Audited
No. conformance conformance
1101 There are documented procedures for the handling of all complaints, recalls and returned product.
11023 There is in place a documented procedure for receiving, recording, reviewing and, where appropriate, acting upon all
quality-related complaints received about veterinary chemical products manufactured or handled on the premises.
The procedure includes the need to consider a recall in the event of a complaint concerning a possible product defect.
1103 Records are kept of all complaints received, investigations carried out and their outcomes and any corrective action
taken to resolve the complaint and prevent the problem happening again.
1104 All complaints related to product quality are registered in a complaints register.
1105 Records should also be kept of all product returned for other reasons, the reason for the return (eg out of date product),
and its disposal. Records are also kept of any required corrective action.
1106 Responsibility for handling complaints related to product quality and for deciding the measures to be taken is
delegated to a specified member or group of staff, who are given adequate resources to carry out the task. If this
person is not the person responsible for quality, the latter are made aware of any such complaint or investigation
involving products manufactured or handled on the premises.
1107 The complaints procedure incorporates the APVMA’s requirements for adverse experience reporting.
Recalls
1101 The APVMA is notified if a manufacturer is considering recall action following possibly faulty manufacture, product
deterioration, or any other serious quality problem with a product. The competent authorities of all countries to which
defective products may have been distributed are also notified.
1100 There is a written procedure for the initiation and management of any recall activity, which is aligned with the
APVMA’s guidelines for the recall of agricultural and veterinary chemical products and the requirements of the Trade
Practices Act. Procedures are regularly checked and updated when necessary.
1112 Responsibility for execution and co-ordination of recalls is delegated to a specific member or group of staff, who are
given adequate resources to handle all aspects of the recalls with the appropriate degree of urgency. This responsible
person is independent of the sales and marketing organisation. If this person is not the person responsible for quality,
the latter is made aware of any recall operation.
1103 Recall operations are capable of being initiated promptly and at any time, including outside normal working hours.
The recalls co-ordinator maintains a regularly updated list of emergency contact numbers, including after-hours
contact details.
1114 Distribution records are readily available to the person(s) responsible for recalls, and should contain sufficient
information on directly supplied customers, including those for exported products.
1115 Recalled products are identified and stored separately in a secure area while awaiting a decision on their fate.
1116 The progress of a recall is recorded and a final report issued, including reconciliation between the delivered and
recovered quantities of products.
1117 Records are kept of all recalls initiated (including internal ‘dummy runs’), all action taken, as well as of details of all
product returned as a result of recalls and its disposal. Records are in accordance with the APVMA’s guidelines for
the recall of agricultural and veterinary chemical products.
Recalls (cont)
Check Checkpoint Acceptable Minor Major Not
Point non non Audited
No. conformance conformance
1118 The effectiveness of the recalls procedure is evaluated from time to time by means of internal ‘dummy runs’ and the
procedure revised if necessary. The outcome of these ‘dummy runs’ is recorded, together with details of any
corrective action considered necessary.
Key observations and comments (Comment on both positive and negative aspects of Complaints and Product Recalls. Record evidence sighted and reviewed, such
as SOPs, records, etc, particularly with respect to non-conformance) .
Manufacturing principles
Veterinary chemical products that are required to be, or are represented as being sterile, must be manufactured:
in separate, controlled areas in the premises that have
- high standards of hygiene
- a system of controlling particulate contaminants appropriate to the class of veterinary chemical product being manufactured
with special care and attention to detail
in accordance with procedures established and validated by the manufacturer.
The manufacturer must establish procedures and have equipment available (or in the case of bioburden, have access to equipment) to adequately monitor:
the microbiological status of the environment in production areas
the microbiological burden of the veterinary chemical products that are to be sterilised.
Premises
Check Checkpoint Acceptable Minor Major Not
Point No. non non Audited
conformance conformance
A1-001 Sterile products are manufactured in areas that are designed and managed to minimise microbial and particulate
contamination.
A1-002 Wherever practicable, enclosed systems are employed for product preparation and filling.
A1-003 Sinks and floor drains are excluded wherever possible. Where this is unavoidable, air breaks are fitted between
the machine and sink or drain.
A1-004 Changing rooms are designed as airlocks and provide physical separation of the different stages of changing to
minimise microbial and particulate contamination of operators and protective clothing.
A1-005 Separate airlocks may be appropriate for moving some materials into controlled areas.
A1-006 An interlocking system or a visual and/or audible warning system is fitted to airlocks to prevent the opening of
more than one airlock door at a time.
A1-007 Under all operational conditions, a filtered air supply to a particular area maintains both a positive pressure and a
positive airflow relative to surrounding areas of a lower grade and flushes the area effectively.
Premises (cont)
Check Checkpoint Acceptable Minor Major Not
Point No. non non Audited
conformance conformance
A1-008 A warning system is provided to indicate failure in the air supply. Indicators of pressure differences are fitted
between areas where these differences are important. These pressure differences are recorded regularly or
otherwise documented.
Production areas
A1-009 Access to buildings is restricted to authorised persons. Visitors are discouraged, kept to a minimum, and generally
permitted only in areas not used for aseptic operations. Visitors’ clothing is in accordance with the area visited.
All production areas are, as far as possible, designed to avoid the entry of non-operational personnel.
A1-010 All exposed surfaces are smooth, impervious and unbroken in order to minimise the shedding or accumulation of
particles or micro-organisms and to permit the repeated application of cleaning agents and disinfectants. Timber
is not used.
A1-011 To reduce accumulation of dust and to facilitate cleaning, there are no uncleanable recesses and a minimum of
projecting ledges, shelves, cupboards and equipment. Doors are designed to avoid uncleanable recesses.
A1-012 Pipes, ducts and other utilities are installed so that they do not create recesses, unsealed openings and surfaces that
are difficult to clean.
A1-013 False ceilings are sealed to prevent contamination from the space above them.
A1-014 Areas for the manufacture of terminally sterilised product are designed to prevent the mixing of sterilised and non-
sterilised products
A1-021 The classification of airborne particulate levels for Grades A-D is given in the following table.
Maximum permitted number of particles/m3 of given size(a)
Notes: (a) A discrete airborne particle counter is used to measure the concentration of particles of sizes equal to or greater than the
designated threshold. Where consideration of particulate contamination is necessary to ensure product quality, a
continuous measurement system are used for monitoring the concentration of particles in the Grade A zone, and is
recommended for the surrounding Grade B areas. For routine testing, the total sample volume are not less than 1/m³ for
Grade A and B areas and preferably also in Grade C areas.
In order to reach the B, C and D air quality grades, the number of air changes are related to the size of the room and the
equipment and personnel present in the room. The air system are provided with appropriate terminal filters such as high
efficiency particulate air (HEPA) filters for grades A, B and C.
(b) The particulate conditions given in the table for the ‘at rest’ state are achieved after a short ‘clean up’ period of 15-20
minutes (guidance value) in an unmanned state after completion of operations. The particulate conditions for grade A ‘in
operation’ given in the table are maintained in the zone immediately surrounding the product whenever the product or
open container is exposed to the environment. It is accepted that it may not always be possible to demonstrate
conformity with particulate standards at the point of fill when filling is in progress, due to the generation of particles or
droplets from the product itself.
(c) The guidance given for the maximum permitted number of particles in the ‘at rest’ and ‘in operation’ conditions
correspond approximately to the cleanliness classes in the AS/NZS ISO 14644-1 at a particle size of 0.5 μm.
(d) These areas are expected to be completely free from particles of size greater than 5 μm. As it is impossible to
demonstrate the absence of particles with any statistical significance, the limits are set to 1 particle/m 3. During the
cleanroom qualification it are shown that the areas can be maintained within the defined limits.
(e) The requirements and limits will depend on the nature of the operations carried out.
A1-022 Other characteristics such as temperature and relative humidity depend on the product and the nature of the operations carried out, as well as on personnel comfort.
These parameters should not interfere with the defined cleanliness standard.
A1-023 Examples of operations to be carried out in the various air quality grades
Environmental monitoring
Check Checkpoint Acceptable Minor Major Not
Point No. non non Audited
conformance conformance
A1-030 Cleanrooms and related areas are monitored at planned intervals for airborne and surface microbiological
contamination and the results obtained used to determine ‘alert’ and ‘action’ levels. Monitoring is frequent and
takes place while normal production operations are in progress. In the case of aseptic filling, it provides the basis
for the assessment of aseptic hygiene throughout the filling process. Results are tabulated or graphed and assessed
and if necessary, prompt remedial action taken according to the standards established. Additional testing is
carried out to determine the effectiveness of such operations as cleaning and fumigation and the influence of
disruptions such as spillage or maintenance.
A1-031 Environmental monitoring of clean areas includes the following components:
(a) particulate monitoring during routine operation, where relevant;
(b) airborne microbiological monitoring;
- air samplers sample an adequate quantity of air to provide a meaningful result (see note a, clause A1-
021);
- air monitoring, using both volumetric and settle plate-sampling methods in aseptic fill and seal areas;
(c) microbiological monitoring of surfaces (eg walls, equipment surfaces, bench tops, trolleys and floors);
(d) microbiological monitoring of personnel (eg external surfaces on gloves, sleeves, and torso);
(e) temperature and humidity monitoring; the recommended settings are 18°C and 35-50% humidity (too high a
value on either setting will promote particulate and microbial shedding from personnel, and too low a setting
will increase static electricity).
A1-032 The methods used for environmental monitoring are justified.
A1-033 Microbiological and particulate contamination are controlled and monitored for each grade by a comprehensive
procedure approved by quality management staff.
A1-034 Media used for environmental monitoring are able to recover yeasts, moulds, fungi and aerobic bacteria.
Monitoring should include anaerobes where the type of product deems this necessary. It is recommended that two
types of culture media (usually agars) be used for the recovery of the above-mentioned organisms.
A1-035 Isolates found during environmental monitoring are regularly identified.
Personnel
Check Checkpoint Acceptable Minor Major Not
Point No. non non Audited
conformance conformance
A1-036 Management delegate the supervision of the production process for sterile products only to persons who are
qualified by training and/or experience in the relevant aspects of pharmaceutical/microbiological sciences. Where
the person responsible for Quality is not a qualified microbiologist, arrangements are made to obtain regular
external expert microbiological advice.
A1-037 All personnel (including those concerned with cleaning and maintenance) receive training in procedures and in
disciplines relevant to the correct manufacture of sterile products, including hygiene (referred to in Chapter 2,
clauses 223-230) and the basic elements of microbiology using expert microbiological advice. When external
personnel who have not received such training (eg building or maintenance contractors) need to be brought in,
particular care is taken over their supervision.
A1-038 Personnel required to work in clean and aseptic areas are selected with care to ensure that they are not subject to
any chronic disease or condition that would present an abnormal microbiological hazard to the product. The same
principle is applied to visitors to clean rooms.
A1-039 Staff who have been engaged in animal handling, processing of animal tissues or products/materials or culturing
of microorganisms other than those used in the current manufacturing process do not enter sterile-product areas
unless rigorous and clearly defined entry procedures have been followed. These entry procedures may include a
period of quarantine exclusion from the manufacturing area.
A1-040 People entering clean areas follow written entry procedures, including changing and hand washing, which are
designed to minimise contamination of clean area clothing or carry-through of contaminants to clean areas.
A1-041 The minimum protective clothing requirements for each grade of controlled area are as follows:
Grade A/B: Headgear should totally enclose hair and, where relevant, beard and moustache; it are tucked into the neck of the suit. A facemask are worn to prevent
the shedding of droplets. Sterilised, non-powdered rubber or plastic gloves and sterilised or disinfected footwear are worn. Trouser-bottoms are tucked
inside the footwear and garment sleeves into the gloves. The protective clothing should shed virtually no fibres or particulate matter and retain particles
shed by the body.
Grade C: Hair and, where relevant, beard and moustache are covered. Non-powdered gloves are worn. A single or two-piece trouser suit, gathered at the wrists and
with high neck and overshoes or dedicated shoes are worn. They should shed virtually no fibres or particulate matter.
Grade D: Hair and, where relevant, beard and moustache are covered. A suitable protective garment and overshoes or dedicated shoes are worn. Gloves (non-
powdered) may be required
Equipment
Check Checkpoint Acceptable Minor Major Not
Point No. non non Audited
conformance conformance
A1-042 Unidirectional airflow equipment is regularly tested and the results recorded.
A1-043 Where necessary, equipment is sterilised before use. The effect of the sterilisation methods on the operation and
durability of equipment is considered. All sterilisation procedures are validated.
A1-044 Equipment used in the processing of sterile products before sterilisation is designed and operated to minimise
contamination by microorganisms and particulate matter. As far as practicable, equipment, fittings and services
are designed and installed so that maintenance and repairs may be carried out without personnel having to enter
the cleanroom. If sterilisation is required, it is carried out after complete reassembly wherever possible.
Maintenance tools and equipment are cleaned, disinfected or sterilised before use.
A1-045 Vessels containing bulk sterile-filtered water or product are vented through bacteria-retaining filters.
A1-046 Autoclaves, gas sterilisers, sterilising ovens, and lyophilisers are equipped with automatic recorders that monitor
the time and temperature and, where necessary, other parameters of the sterilising cycle. This equipment is
qualified upon installation and is calibrated periodically. Records confirm that these parameters have been
achieved with an appropriate degree of accuracy.
A1-047 A temperature-sensing probe for the automatic temperature recorder is located at the position in the steriliser
shown by previous studies to be the coolest part of the loaded chamber. Where sterilisers are fitted with a drain at
the bottom of the chamber, it may also be necessary to record the temperature at this position throughout the
sterilisation period. There are regular leak tests on the chamber when a vacuum phase is part of the cycle.
A1-048 Heat sterilisers have provision for the entry of leads from temperature sensing devices placed in product packs or
simulated product packs during heat penetration studies.
A1-049 The pressure during steam sterilising cycles is recorded at least manually.
A1-050 Steam used for sterilisation does not contain additives at a level that could cause contamination of product or
equipment. The use of ‘clean steam’ may need to be considered.
A1-051 Where the quality of the product may be affected, air or any other gas admitted to an autoclave, hot air steriliser or
lyophiliser or used to promote positive pressure for filtration, is filtered through a bacteria-retaining filter.
Compressed air used is also filtered through a bacteria-retaining filter.
A1-052 Water treatment plants and distribution systems are designed, constructed and maintained so as to ensure a reliable
source of water of an appropriate quality. They are not operated beyond their designed capacity. Water is
produced, stored and distributed in a manner that prevents microbial growth; for example, by constant circulation
at a temperature above 80°C or at 4°C or below.
Equipment (cont)
Check Checkpoint Acceptable Minor Major Not
Point No. non non Audited
conformance conformance
A1-053 All water systems supplying processed water for product manufacture are monitored for:
(a) total organic carbon;
(b) conductivity;
(c) endotoxin;
(d) microbial quality.
Processing
A1-057 Containers or other materials liable to generate particles or fibres are not taken into areas supplied with Grade A,
B or C air.
A1-058 The intervals between the washing, drying and sterilisation of components, containers and equipment is as short as
possible and subject to a time limit appropriate to the storage conditions. The interval between sterilisation and
the use of these materials is also subject to a time limit.
A1-059 The time between the start of the preparation of a solution and its sterilisation is as short as possible and subject to
a limit for each product that takes into account its composition and the prescribed method of storage. Unless
special storage conditions are provided, bulk aqueous solutions have no greater volume than can be used in one
working day and are filled into final containers and sterilised within one working day.
A1-060 The microbiological load of products is as low as practicable before sterilisation. It is monitored and an action
level set that is related to the efficiency of the method of sterilisation to be used, the risk of pyrogens and previous
validation results. All solutions and in particular, large volume infusion fluids are passed through a filter of pore
size ≤ 0.45 μm, where possible immediately before filling.
Processing (cont)
Check Checkpoint Acceptable Minor Major Not
Point No. non non Audited
conformance conformance
A1-061 Batch processing records for sterile products include details of the sterilisation of the batch and, where the batch is
aseptically processed, details of the sterilisation of the components and equipment used.
A1-062 The charts of automatic recorders of cycle parameters constitute part of the batch processing records of sterile
products and are marked to identify the batch or batches to which each applies.
A1-063 Sterilisation records are reviewed and approved as part of the batch release procedure.
A1-064 Each separate sterilising basket, package, pallet, etc, of products or components undergoing sterilisation is
fastened, wired, sealed, lidded or otherwise secured to prevent mix-up. It bears, in a conspicuous position, a
visual indicator to demonstrate whether it has passed through a sterilisation cycle.
A1-065 Microbiological indicators are quarantined and subjected to quality control before use.
A1-066 Preparations of microbiological origin are not be made or filled in areas used for the processing of other medicinal
products, unless justified by a written risk analysis.
A1-067 Components, containers and equipment are handled after the final cleaning process in such a way that they are not
re-contaminated.
A1-068 Each procedure used for the sterilisation of a particular quantity or volume of a material component or product has
been shown by validation studies to be effective and reliable. The validation is verified at scheduled intervals
based on performance history, or when any significant change is made in the process or equipment.
A1-069 Where practicable, heat sterilisation is the method of choice. In any case, the sterilisation process is in accordance
with product registration.
A1-070 Validated loading patterns are established for all sterilisation processes.
A1-071 Biological indicators are considered as an additional method for monitoring the sterilisation process. They are
stored and used according to the manufacturer’s instructions, and their quality checked by positive controls. If
biological indicators are used, strict precautions are taken to avoid transferring microbial contamination from them
Sterilisation by radiation
A1-079 The radiation dose is measured during the sterilisation procedure. For this purpose, dosimetry indicators that are
independent of dose rate are used, giving a quantitative measurement of the dose received by the product itself.
These dosimeters are inserted in the load in sufficient number, close enough together to ensure that there is always
a dosimeter in the irradiator. The position in the carrier receiving the lowest dose and where appropriate, the
highest dose are represented. Where plastic dosimeters are used, they are used within the time limit of their
calibration. Dosimeter absorbances are read soon after exposure to radiation.
A1-080 Biological indicators may be used as an additional control.
Sterilisation by filtration
Check Checkpoint Acceptable Minor Major Not
Point No. non non Audited
conformance conformance
A1-090 Solutions or liquids are filtered through a sterile filter of nominal pore size of ≤0.22 μm, or with at least equivalent
micro-organism retaining properties, into a previously sterilised container. Consideration is given to
complementing the filtration process with heat or other treatment where the presence of filterable microorganisms
is suspected.
A1-091 Positive pressure rather than negative pressure is used in filtration processes. To enhance the assurance of
sterility, a second filtration step immediately before filling, may be advisable.
A1-092 Fibre-shedding characteristics of filters are minimal. Asbestos-containing filters are not used under any
circumstances.
A1-093 The same filter is not used for more than one working day, unless such use has been validated.
A1-094 The filter does not affect the product by removal of ingredients from it or by release of substances into it.
A1-095 The integrity of the sterilised filter is verified immediately after use by an appropriate method, such as a bubble
point, diffusive flow or pressure hold test. Integrity testing before and during use should also be considered. The
time taken to filter a known volume of bulk solution and the pressure difference to be used across the filter, are
determined during validation and any significant variation from this during routine manufacturing is noted and
investigated. Results of these checks are included in the batch record. The integrity of critical gas and air vent
filters is confirmed after use. The integrity of other filters is confirmed at appropriate intervals.
Quality control
Check Checkpoint Acceptable Minor Major Not
Point No. non non Audited
conformance conformance
A1-099 Where required or appropriate, tests for the following are carried out on each batch of product. For injectable and
large volume infusion solution products, such testing is essential:
(a) sterility;
(b) uniformity of contents;
(c) potency;
(d) pyrogenicity or endotoxin;
(e) particulate matter.
A1-100 Cumulative records of environmental control, the testing of manufacturing equipment, media fill runs and all other
applicable quality control tests are maintained by Quality Control.
A1-101 Pharmacopoeial methods are used for sterility tests. These methods are validated for the product(s) concerned.
A1-102 Where parametric release has been authorised, all calibrations and controls that were specified in the application
for authorisation are rigorously maintained.
A1-103 Samples taken for sterility testing are representative of the whole of the batch, and include samples taken from
parts of the batch considered to be most at risk of contamination, for example:
(a) for products that have been filled aseptically, samples include containers filled at the beginning and end of
the batch and after any significant intervention;
(b) for products that have been heat sterilised in their final containers, samples are taken from the potentially
coolest part of the load.
A1-104 Release of sterile product includes a review of:
(a) validation studies, including, in the case of aseptic filling, media fill results;
(b) environmental monitoring results;
(c) batch records including in-process test results;
(d) equipment monitoring and performance records;
(e) finished product test records.
Aseptic processing
Premises
Check Checkpoint Acceptable Minor Major Not
Point No. non non Audited
conformance conformance
A1-105 Aseptic filling involves the minimum of human intervention.
A1-106 Sinks and drains are excluded from aseptic filling/sealing rooms.
A1-107 Airlocks are flushed effectively with filtered air. The final stage of the changing room is, in the ‘at rest’ state, the
same grade as the area into which it leads. Separate changing rooms for entering and leaving clean areas are
provided where desirable. Hand-washing facilities are provided only in the first (outer) stage of the changing
rooms.
A1-108 Adjacent rooms of different grades have a pressure differential of 10-15 pascals (guidance values). The air-flow
pattern, location of equipment and movement of personnel affords protection of the zone of greatest risk (ie the
immediate environment to which a product and sterilised components that contact the product are exposed).
Production areas
A1-109 Products are manufactured in a clean area up to the stage where they are sterilised, and thereafter processed and
filled into their final containers under aseptic conditions, employing a double barrier system. The first barrier is
provided by unidirectional flow workstations in which the actual filling operations are carried out. The second
barrier is provided by the supply of filtered air into the room in which the operations are carried out. It is
desirable to maintain this room at a positive pressure relative to the outside environment.
A1-110 Non-sterile products are not processed in the same area as sterile products.
A1-111 Grade B areas (see clause A1-020) are designed so that all operations can be observed from the outside.
and restrict the passage of particulate matter. These garments are not fitted with pockets or cuffs.
Environmental control
A1-116 The ‘in operation’ and ‘at rest’ states are defined for each clean room or suite of clean rooms.
A1-117 Examples of operations to be carried out in the various clean zone grades
Grade Operations for aseptic preparations
A Preparation of solutions that are not to be filtered.
Handling of sterile starting materials and components that are not to be filtered.
Handling and filling of aseptically prepared products.
Transfer of partially closed containers, as used in freeze drying.
Preparation and filling of sterile ointments, creams, suspensions and emulsions.
B Transfer of partially closed containers in sealed transfer trays.
C Preparation of solutions to be filtered.
D Handling of components after washing.
Environmental monitoring
A1-118 Sampling methods used during operation do not interfere with zone protection. Results from monitoring are
considered when reviewing batch documentation for finished product release. Surfaces and personnel are
monitored after critical operations.
A1-119 Additional microbiological monitoring may be appropriate after activities such as major maintenance, interruption
to production and equipment validation.
A1-120 Recommended limits to be used in microbiological monitoring of clean areas (a) during operation:
Sampling method
Grade Air sample Settle plates (diam. Contact plates Glove print
cfu/m3 90mm) cfu/4 hours (diam. 55mm) (5 fingers)
(b)
cfu/plate cfu/glove
A <1 <1 <1 <1
B 10 5 5 5
C 100 50 25 -
D 200 100 50 -
Personnel
A1-122 Only the minimum number of personnel essential for production and in-process control operations are allowed in
aseptic or clean areas, particularly during aseptic processing. Inspections and controls are conducted outside the
clean areas as far as possible.
A1-123 Personnel engaged in servicing equipment or other non-routine activities observe the same precautions and
hygiene standards as production personnel.
A1-124 Wrist watches, make-up and jewellery are not worn in clean areas.
A1-125 Outdoor clothing is not brought into changing rooms leading to Grade B and C rooms. Clean sterile (sterilised or
adequately sanitised) protective garments are provided at each work session for every worker in a Grade A/B area.
Gloves are regularly disinfected during operations. Masks and gloves are changed at least at every working
session.
Personnel (cont)
Check Checkpoint Acceptable Minor Major Not
Point No. non non Audited
conformance conformance
A1-126 Clean area clothing is cleaned and handled in such a way that it does not gather additional contaminants that can
later be shed. These operations follow written procedures. Separate laundry facilities are provided for such
clothing.
Equipment
A1-127 A conveyor belt should not pass through a partition between a Grade A or B area and a processing area of lower
air cleanliness, unless the belt itself is continually sterilised (eg in a sterilising tunnel).
Processing
A1-128 Activities in clean areas, especially when aseptic operations are in progress, are kept to a minimum and movement
of personnel is controlled and methodical to avoid excessive shedding of particles and organisms as a result of
over-vigorous activity. The ambient temperature and humidity are set to provide a comfortable environment,
taking into account the nature of the garments worn.
A1-129 Components, containers, equipment and any other article required in a clean area where aseptic work takes place
are sterilised and passed into the area through double-ended sterilisers sealed into the wall, or by a procedure that
achieves the same objective of not introducing contamination. Non-combustible gases are passed through
microorganism-retentive filters.
A1-130 Validation of aseptic processing includes a process simulation test using a nutrient medium (media fill). The
process simulation test imitates as closely as possible the routine aseptic manufacturing process, including
predictable interventions and worst-case situations. Process simulation tests are performed as an initial validation
with three consecutive satisfactory simulation tests per shift and then repeated at defined intervals (not less than
once annually) and after any significant modification to the heating, ventilation and air conditioning (HVAC)
system, equipment, process or number of shifts. The number of containers used for media fills is sufficient to
enable a valid evaluation. For small batches, the number of containers for media fills is at least equal to the size of
the product batch. The target is zero growth, but production need not be halted if a contamination rate of less than
0.1% is observed. The manufacturer has establish alert and action limits.
A1-131 Care is taken that any validation does not compromise the processes
Key observations and comments (Comment on both positive and negative aspects of Sterile Product manufacture. Record evidence sighted and reviewed, such as
SOPs, records, observations, etc, particularly with respect to non-conformance) .
Manufacturing principles
Veterinary immunological products and other chemical products of biological origin, including those that are manufactured using a specified biological process, must be
manufactured:
using only biological starting materials that are, or are derived from biological materials demonstrated to be as free as practicable from adventitious contamination;
in premises designed, constructed and maintained so as to provide an appropriate level of containment of the biological or microbiological agents being handled and to
permit effective decontamination from these agents or from toxic residues by procedures that
- are established and validated by the manufacturer
- maintain the safety of personnel
in cases where uniformity of product depends on deriving batches from a seed lot
- by maintaining the lots in secure and protective storage
- by keeping meticulous records of their origin and disposition .
Premises-general
Check Checkpoint Acceptable Minor Major Not
Point No. non non Audited
conformance conformance
A2-001 Documentation relating to the premises is readily available, including a detailed description (with plans and
explanatory notes) of the manufacturing site and buildings, showing the designation and conditions of use of all
rooms as well as the biological agents that are handled in them. The flow of people and product is clearly marked.
A2-002 Animal species accommodated in animal houses or otherwise on the site are identified on the site plans or
accompanying notes.
A2-003 Activities carried out in the vicinity of the site are also indicated on the site plans or accompanying notes. Plans of
clean or contained areas describe the ventilation system, indicating inlets and outlets, filters and their
specifications, the number of air changes per hour and pressure differentials. They indicate which pressure
differentials are monitored by pressure indicators.
Personnel
Check Checkpoint Acceptable Minor Major Not
Point No. non non Audited
conformance conformance
A2-017 In the case of biological agents known to cause disease in humans, adequate measures are taken to prevent
infection of personnel working with live organisms or with animals. Where relevant, personnel are appropriately
vaccinated and subject to regular medical examination.
A2-018 Adequate measures are taken to prevent biological agents being carried outside the manufacturing plant by
personnel. Dependent on the type of biological agent, such measures may include complete changing of clothes
and compulsory showering before leaving the production area.
A2-019 Prevention of product contamination by personnel is achieved by a set of measures and procedures that ensure that
appropriate protective clothing is used during the different stages of the production process. Personnel do not pass
from one area to another unless they have taken appropriate measures to eliminate the risk of contamination.
A2-020 Only personnel essential for production and in-process control operations, maintenance and cleaning are allowed
into processing areas.
A2-021 Personnel working in areas designated as ‘clean/aseptic’ or ‘culturing’ change into clean over-garments before
moving from one area to another, and the over-garments are removed on exit from the relevant area. The same
principles apply when staff move from other areas into clean/aseptic or culturing areas.
Equipment
A2-022 Any closed equipment used for the primary containment of biological agents is designed and constructed to
prevent any leakage or the formation of droplets and aerosols. Inlets and outlets for gases are protected to achieve
adequate containment (eg by the use of sterilising hydrophobic filters). The introduction or removal of material
takes place using a sterilisable closed system, or possibly in an appropriate unidirectional air flow.
A2-023 Separate incubators are used for infected and non-infected containers and also generally for different organisms or
cells. Incubators containing more that one organism or cell type will only be acceptable if adequate measures are
in place to seal, surface decontaminate and segregate the containers. All containers are individually labelled.
Equipment used for the storage of biological agents or products is designed and used in such a manner as to
prevent any possible mix-up. All stored items are clearly and unambiguously labelled and kept in leak-proof
containers. Items such as seed stock (cell or organism) are stored in dedicated equipment.
A2-024 For single-ended freeze-driers, the clean room is decontaminated at the end of the process and before a further
manufacturing batch is introduced into the area, unless this contains the same organisms. Double-door freeze-
driers are sterilised after each cycle unless opened in a clean area. Sterilisation of freeze-driers is done at least
after each campaign.
Equipment (cont)
Check Checkpoint Acceptable Minor Major Not
Point No. non non Audited
conformance conformance
A2-025 Equipment used in the culturing of microorganisms is capable of decontamination, either in situ or otherwise, and
is capable of effective cleaning before re-use and/or sterilisation.
A2-026 In heat sterilising processes, steps are taken to ensure that the whole load reaches the sterilisation temperature.
Account is taken of heat-up times for various loads and ‘typical loading’ diagrams are part of standard operating
procedures. Standard operating procedures are available.
A2-027 Items to be sterilised by autoclaving are wrapped in a material that allows the removal of air (either by free steam
or evacuation of the chamber) and its replacement by steam, but does not permit recontamination when dry.
A2-028 Sterilisation by filtration should not be used when sterilisation by heat is acceptable. Positive pressure rather than
negative pressure is used in filtration processes. The integrity of the filter system is tested immediately after each
use.
A2-029 When re-useable filters are used, they are effectively cleaned and sterilised after each use. Consideration is given
to using individual filters for one type of solution only.
A2-030 Unidirectional airflow equipment is regularly tested and the results recorded. Cleanrooms and related areas are
monitored at planned intervals for microbiological contamination.
Production - general
Check Checkpoint Acceptable Minor Major Not
Point No. non non Audited
conformance conformance
A2-036 Production of biological agents may take place in either clean or controlled areas, provided it is carried out in
totally enclosed and heat sterilised equipment, with all connections being also heat sterilised after making and
before breaking. It may be acceptable for connections to be made under local unidirectional airflow, provided
these are few in number and proper aseptic techniques are used and there is no risk of leakage. The sterilisation
parameters used before breaking the connections are validated for the organisms being used. Different products
may be placed in different bioreactors within the same area, provided that there is no risk of accidental cross-
contamination. However, organisms generally subject to special requirements for containment are in areas
dedicated to such products.
A2-037 Critical procedures, including methods for sterilisation, disinfection, virus removal and inactivation, are validated
and subject to monitoring and in-process controls.
A2-038 Substances of animal origin are prepared from homogeneous bulk material, designated with a batch number. A
batch may contain material derived from as many animals as is desired, but once designated and given a batch
number, a batch is not added to or contaminated in any way.
Production - media
A2-042 Media used in fermenters or bioreactors is sterilised in situ or in line, preferably by heat. Gases, media, acids,
alkalis, defoaming agents and other materials introduced into sterile bioreactors are themselves sterile.
A2-043 Where heat-labile media components are required, these are sterilised by other acceptable means (eg filtration,
gamma irradiation) and added aseptically to the heat-sterilised base medium.
Quality control
A2-065 In-process controls that are crucial to product quality, but which cannot be carried out on the finished product, are
performed at an appropriate stage of production.
A2-066 Where testing of bulk or intermediate materials is required, a sufficient quantity of sample is retained, under
appropriate storage conditions, to allow repetition or confirmation of the test result if necessary.
A2-067 Where production of a biological product involves continuous culture, the quality control requirements arising
from such a production method are appropriately addressed.
A2-068 Sufficient quality control testing is undertaken to ensure that the product complies with the approved registration
particulars.
A2-069 Quality Control maintains cumulative records of environmental control, the testing of manufacturing equipment
and all other quality control tests where applicable, and takes into account the results of such testing before
releasing any batch of product for distribution.
Key observations and comments (Comment on both positive and negative aspects of the manufacture of Immunobiological and other Biological products. Record
evidence sighted and reviewed, such as SOPs, records, observations, etc, particularly with respect to non-conformance) .
Key observations and comments (Comment on both positive and negative aspects of Non-Sterile Therapeutic product manufacture. Record evidence sighted and
reviewed, such as SOPs, records, observations, etc, particularly with respect to non-conformance) .
Key observations and comments (Comment on both positive and negative aspects of Herbal product manufacture. Record evidence sighted and reviewed, such as
SOPs, records, observations, etc, particularly with respect to non-conformance) .
ANNEX 5 ECTOPARASITICIDES
Check Checkpoint Acceptable Minor Major Not
Point No. non non Audited
conformance conformance
A5-001 Ectoparasiticides are made in segregated areas or separate buildings, using equipment that is dedicated to this type
of product. Use of common equipment may be accepted, provided that cross-contamination is controlled by
scheduling and use of a validated cleaning procedure.
A5-002 Where ectoparasiticides are manufactured in a facility that also manufactures agricultural chemicals, they are
made in a separate area of the plant, using equipment dedicated to veterinary chemical manufacture. Special
measures are taken to prevent cross-contamination with agricultural chemicals, particularly where shared
facilities, such as packing rooms, are used.
A5-003 Bunding is used where necessary to meet the requirements of dangerous goods and environment protection
legislation.
A5-004 Where high volume materials (eg solvents in 200 litre drums) are stored out-doors, they are in adequately sealed
containers and outside storage conditions are unlikely to adversely affect their quality.
A5-006 Manufacturing processes that involve the application of a liquid premix onto an inert carrier powder ensure
adequate dispersion of the liquid and, therefore, the active ingredient(s). Mixing times and methods ensure batch
homogeneity.
A5-007 Measures are in place to prevent cross-contamination from hoses, fixed pipe-work and connections
Key observations and comments (Comment on both positive and negative aspects of Ectoparasiticide manufacture. Record evidence sighted and reviewed, such as
SOPs, records, observations, etc, particularly with respect to non-conformance) .
Key observations and comments (Comment on both positive and negative aspects of the manufacture of Premixes, Supplements and Biological Feed Additives.
Record evidence sighted and reviewed, such as SOPs, records, observations, etc, particularly with respect to non-conformance) .