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MANUFACTURERS LICENSING SCHEME

GMP Audit Checklist for MANUFACTURERS


Form: KP80_F33

Company Name

Date of Audit

Audit Conducted By

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) !ttention to the matters on this checklist will assist manufacturers to meet their obligations in upcoming GMP audits "ach item in the checklist should be assessed for level of compliance with the GMP #ode$ using the following criteria% Acceptable & satisfactory or substantial compliance with the GMP #ode' Minor non-conformance ( minor or less serious non&conformance which may not pose a risk to product )uality' Major non-conformance ( failure to satisfy a key or mandatory re)uirement and*or one which may pose a risk to product )uality' 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)

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CORE ELEMENT 1 Manufacturin% principle&

!AL"T# MANA$EMENT

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 ris! due to inadequate quality safety or efficacy. The quality assurance system must ensure that" appropriate procedures are in place to ensure that relevant quality standards are met all materials involved in the manufacturing process comply with required quality standards before they are released for use in manufacture there are measures designed to prevent cross-contamination there are safeguards and controls in place designed to prevent the occurrence of foreseeable errors or process failures finished products have been made and stored correctly and they comply with required quality standards before they are released for supply. The quality assurance system must be relevant to the nature and intended use of the product. #t must be fully documented monitored for effectiveness and provide for continuous improvement.

Mana%ement of 'uality
C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

-.-.1 -.2

/ocumented )uality assurance system$ supported by management$ in place 0uality re)uirements are understood$ implemented and maintained at all levels of the organisation !de)uate resources provided to achieve this ! senior manager has responsibility for the overall direction and management of )uality within the organisation Management reviews the )uality assurance system at stated$ regular intervals (no greater than every three years)$ to ensure the continued suitability$ ade)uacy and effectiveness of the system$ and its continual improvement That review evaluates any changes to the )uality system that have taken place Management review process documented and records of the review maintained

uality a&&urance
-.3 The )uality assurance system ensures that% (a) managerial responsibilities are clearly defined$ documented and exercised'

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C(ec) *oint No+

C(ec)point

Acceptable

Minor non conformance

Major non conformance

Not Audited

(b) (c) (d) (e) (f)

production and control operations are clearly specified and good manufacturing and good laboratory practices are followed' starting and packaging materials meet re)uired specifications utilising vendor assurance where possible' all necessary controls on intermediate products and in&process controls are carried out' all necessary validations are carried out' finished products are not supplied before an authorised person has certified that each batch has been produced in accordance with documented procedures$ meets re)uired specifications that are consistent with product registration$ and meets all re)uired )uality tests' appropriate environmental and storage conditions are maintained' there is a procedure for conducting internal )uality audits (self inspections) that regularly appraise the effectiveness and application of the )uality assurance system

(g) (h)

uality control
-.4 ! system of )uality control is in place to ensure that products comply with their re)uired specifications and standards$ as described in #hapter 5 of the GMP #ode

uality and production nominee&


-.6 The responsibilities for 0uality and for Production are allocated to specific persons Those nominated for these responsibilities are$ where practicable$ different persons$ neither responsible to the other They are suitably )ualified$ trained or experienced as described in #hapter 1 of the GMP #ode The persons responsible for Production and 0uality have effective control over any manufacturing steps carried out at all premises covered by the manufacturing licence The person nominated as being responsible for Production has the necessary authority to control manufacture of the product The usual duties of that person are described more fully in #hapter 1 of the GMP #ode The person nominated as being responsible for 0uality has the necessary independence and authority to ensure that )uality measures are employed in the production and testing of product and that product is not released until judged to be satisfactory The usual duties of that person are described more fully in #hapter 1 of the GMP #ode

-.7 -.5 -.8

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C(ec) *oint No+

C(ec)point

Acceptable

Minor non conformance

Major non conformance

Not Audited

--.

9here operational events and )uality policy conflict$ the person nominated as being responsible for 0uality has the authority to make a decision to resolve the conflict :uch circumstances and the decision are recorded

*roce&& control and c(an%e control


----1 !ll critical steps in the manufacturing process$ and any changes to these steps$ are documented Manufacturing processes are reviewed at defined regular intervals and the outcome of that review is documented and acted upon ! change control system is in place to manage significant manufacturing and product )uality changes This includes provision to notify the !P;M!$ as the registration authority$ of variation in product details where necessary

,ey ob&er-ation& and comment& .Comment on bot( po&iti-e and ne%ati-e a&pect& of uality Mana%ement+ Record e-idence &i%(ted and re-ie/ed0 &uc( a& policy document&0 record&0 etc0 particularly /it( re&pect to non-conformance1 +

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CORE EMEMENT 2 Manufacturin% principle&

*ER3ONNEL AND TRA"N"N$

Veterinary chemical products must be manufactured under the management and supervision of appropriately qualified trained or e$perienced 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. Manufacturing staff must be trained to a satisfactory level of competency in" the basic principles of good manufacturing practice the specific duties in connection with the manufacture of veterinary chemical products that they are required to perform. There must be a sufficient number of competent personnel to carry out all required tas!s.

$eneral
C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

1.1.1 1.2 1.3 1.4 1.6

The manufacturer has an ade)uate number of personnel with the necessary )ualifications$ training or practical experience The responsibilities placed on any one individual are not so extensive as to present a risk to )uality The manufacturer has an organisational chart showing the names of key personnel$ as well as their areas of responsibility and lines of authority 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 People in responsible positions have ade)uate authority to carry out their responsibilities 9here the duties of persons in responsible positions are delegated to designated deputies with relevant )ualifications and experience$ records are kept of those delegations <perators= verbal and written communication skills are sufficient for them to respond to training$ accept and implement instructions exactly and$ where their duties re)uire it$ fill out forms correctly

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,ey per&onnel
C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

1.7

>ey personnel include the persons nominated as responsible for Production and for 0uality and$ if neither of these persons is responsible for product release$ the person(s) authorised for that purpose >ey positions are occupied by full&time personnel The persons responsible for Production and for 0uality are independent from each other ?n small operations where this may not be possible$ the )uality control function and procedures are clearly documented and shown to be effective The person with overall responsibility for Production has responsibility to% (a) (b) (c) (d) (e) (f) (g) ensure that products are produced and stored according to documented procedures approve procedures relating to production operations and ensure their strict implementation approve and monitor any subcontracted production work ensure that production records are evaluated and signed by an authorised person before they are submitted for product release ensure that production areas$ premises and e)uipment are maintained to an appropriate standard ensure that appropriate validations are conducted ensure that initial and continuing training of production personnel are conducted$ according to need

1.5

1.8

1-.

The person with overall responsibility for 0uality has responsibility to% (a) (b) (c) (d) (e) (f) (g) (h) (i) evaluate and authorise master manufacturing and packaging documents approve specifications$ sampling instructions$ test methods and other )uality control procedures approve or reject raw materials$ packaging materials$ and intermediate$ bulk and finished products review completed batch records as part of the release procedures ensure that all necessary testing is carried out approve and monitor any contract analysts monitor )uality performance of subcontract manufacturers check the maintenance of the )uality control area$ premises and e)uipment ensure that appropriate validations are conducted
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,ey per&onnel .cont1


C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

(j) (k)

ensure that initial and continuing training of )uality control personnel are conducted$ according to need approve and monitor the suppliers of materials

<ther duties relating to )uality control are summarised in #hapter 5 of the GMP #ode 1-9here the persons responsible for Production and 0uality have some shared or jointly&exercised responsibilities$ their primary roles are not compromised

ualification& and e4perience


1-1 The persons responsible for Production and 0uality have a relevant scientific )ualification at tertiary level and*or have had relevant practical experience and the necessary competencies in the manufacture of products in accordance with GMP re)uirement

Trainin% and competency a&&e&&ment


1-2 Training provided for all personnel whose duties take them into production areas or into )uality control laboratories$ including technical$ maintenance and cleaning personnel Training also given to other personnel whose activities could affect product )uality Particular attention given to the training needs of casual employees Training programs are appropriate to the identified needs of staff and are approved by the head of either Production or of 0uality$ as appropriate The effectiveness of the training program is monitored Training programs include initial training in the basic principles of GMP$ as well as training appropriate to the duties assigned to staff Programs also include ongoing training and refresher training$ including training in changes to the manufacturing process and procedures Training programs specifically address the concept of )uality assurance$ as well as relevant aspects of sanitation and personal hygiene @ecords are kept of all internal and external training programs and the various training activities undertaken by individual staff :taff are assessed for their competence to perform the duties assigned to them @ecords are kept of those assessments Personnel working in areas where contamination is a haAard (eg cleanrooms or areas where highly active$ toxic$ infectious or sensitising materials are handled) are given specific training in those aspects of manufacture Personnel have a clear understanding of their responsibilities

1-3 1-4

1-6 1-7 1-5 1-8

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Trainin% and competency a&&e&&ment .cont1


C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

11. 11111

Personnel are not be re)uired to$ or allowed to$ sign or initial a document unless they have been trained and assessed as competent in the work practices associated with the signature and in the significance of the signature ! register of staff signatures and initials is maintained "ntries are updated at regular stated intervals and the previous records archived ;isitors or untrained personnel are not normally taken into active production and )uality control areas ?f access is unavoidable$ they are ade)uately supervised and given information in advance$ particularly about personal hygiene and prescribed protective clothing

*er&onal (y%iene and (ealt( i&&ue&


112 /etailed hygiene programs are established and adapted to meet the needs of the different areas within the manufacturing facility They include procedures relating to the health$ personal hygiene practices and clothing of staff These procedures are understood and followed by every person whose duties take them into the production and )uality control areas 9here relevant$ production personnel are subjected to medical examination to ensure that their health status does not pose a risk to product )uality and that they are able to carry out re)uired tasks (eg visual checks of labels or containers) :taff are made aware of the need to draw management=s attention to any health problems that might affect product )uality :teps are taken to ensure that anyone affected by an infectious disease$ or having open lesions on an exposed surface of the body$ is not engaged in activities where operator&borne contaminants may pose a risk to product )uality "very person entering the manufacturing or )uality control areas wears protective garments appropriate to the operations carried out there Protective clothing is cleaned and*or replaced at fixed intervals or when soiled$ and kept in good condition 9hen necessary$ soiled clothing is decontaminated before being laundered (eg clothing from areas where live microorganisms are being cultured) 9here garments are laundered off&site$ any special precautions re)uired to avoid harm to personnel or the environment are specified Protective clothing is not be worn outside the factory premises "ating$ drinking$ chewing$ smoking$ or the storage of food$ drink$ smoking materials or personal medication is not allowed in the production$ packaging$ storage$ or laboratory areas @elevant signs are displayed at prominent positions at entry points to these areas

113

114

116 117

115

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*er&onal (y%iene and (ealt( i&&ue& .cont1


C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

118 12.

/irect contact is avoided between the operator=s hands and the exposed product or any part of the e)uipment that comes into contact with the product The wearing of jewellery that may become detached or caught in machinery is discouraged in manufacturing areas

,ey ob&er-ation& and comment& .Comment on bot( po&iti-e and ne%ati-e a&pect& of *er&onnel and Trainin%+ Record e-idence &i%(ted and re-ie/ed0 &uc( a& policy document&0 3O*& and record&0 particularly /it( re&pect to non-conformance1 +

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CORE ELEMENT 5 Manufacturin% principle&

B!"LD"N$3 AND $RO!ND3

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 ris! 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 ris! 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.

$eneral
C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

2.-

Premises are situated in an environment that presents minimal risk of causing contamination of materials or products (Bor 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) The premises$ including the surrounding grounds and gardens$ are kept in an orderly$ neat and tidy condition 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 #avities and voids are minimised and$ where necessary$ provided with access for pest control purposes "ach part of the premises is suitable for the operations being carried out and kept in good repair @epair and maintenance operations do not present any haAard to product )uality Cighting$ temperature$ humidity and ventilation are appropriate for the type of operations being undertaken They do not directly or indirectly$ adversely affect product )uality during manufacture and storage$ or the accurate functioning of e)uipment !ir intakes are located away from sources of contamination :inks are made of stainless steel$ without overflow and preferably spaced 4. mm away from walls so as to avoid uncleanable joins and crevices 9here appropriate$ they have effective$ easily cleanable traps and air breaks to prevent backflow

2.1 2.2

2.3 2.4

2.6

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Buildin%& and %round& 6 %eneral .cont1


C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

2.7

Bloor drains are generally avoided 9here necessary$ they are of ade)uate siAe$ flush with the floor$ screened and trapped /rains are underground <pen channels generally avoided$ but$ if necessary$ are shallow to facilitate cleaning and disinfection Production and )uality control areas are not used as passageways by personnel who do not work in them$ or for the transport of materials not being currently used in them They are not used as storage areas for obsolete materials or e)uipment The premises are secured against entry of unauthorised personnel or materials ;isitors to the premises$ including external maintenance workers and contractors$ are supervised and restricted to an appropriate level of access

2.5

2.8

Cleanin% and &anitation


2-. 2-Processing areas$ laboratories and storage areas are kept in a clean$ sanitary and orderly condition /ocumented cleaning procedures are available for all areas These describe% (a) (b) (c) 2-1 the areas to be cleaned$ the fre)uency of cleaning$ and specific re)uirements of individual areas' the materials$ concentrations and e)uipment to be used' the methods used to decontaminate cleaning e)uipment

9here the removal of traces of product is critical$ evidence to demonstrate that the cleaning process is effective is available. %#n these cases unless standards of cleanliness are prescribed by a regulatory authority manufacturers should determine appropriate limits based on assessed ris!& 9aste material are deposited in suitable$ appropriately located and labelled containers and appropriately disposed of at fre)uent intervals 9here necessary$ effluent is treated before disposal The premises are kept free of insects$ birds$ rodents$ and other animals$ either by containment or by appropriate control measures ! documented pest control program is in place$ which is monitored for effectiveness @ecords describe the location of bait stations$ materials used$ monitoring fre)uency and effectiveness

2-2 2-3

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3tora%e area& .includin% receipt and de&patc( 1


C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

2-4

:torage areas are organised and of sufficient area to permit the effective separation and identification of the various materials and products stored in them Materials or products that are rejected$ returned or recalled are segregated and secured :torage areas provide storage conditions appropriate to the materials and products held in them ?n particular$ they are clean$ dry$ and maintained within acceptable temperature limits 9here special storage conditions are re)uired (eg temperature and humidity) these are provided and monitored %'ote that these requirements do not preclude outdoor storage of materials where outdoor storage does not adversely affect quality& 9here a controlled storage temperature is critical for the maintenance of material or product )uality$ the environment is controlled$ monitored and recorded$ as follows% (a) (b) there are temperature recording devices$ and records are under regular review' there is an alarm and*or visual signal to indicate that a storage temperature control system has failed' the system permits resetting only by authorised personnel and is checked at regular$ stated intervals

2-6

2-7

2-5 2-8 21. 21211 212

@efrigerators$ cold rooms and freeAers are regularly defrosted and cleaned ?n the event that a refrigeration storage facility is shut down$ total cleaning occurs @eceiving and despatch bays protect materials and products from the weather and are designed and e)uipped to allow containers of incoming materials to be cleaned$ where necessary$ before storage <n receipt$ all starting materials (including labels$ printed cartons and other packaging material) are subject to effective )uarantine and release control 9here )uarantine status is ensured by storage in separate areas$ these areas are clearly marked !ny system replacing a physical )uarantine system (such as a computerised access system) provides at least an e)uivalent level of security :ampling of raw materials is conducted in such a way that contamination of the material$ or cross&contamination of other materials$ is prevented There is a separate sampling area for highly active$ haAardous or toxic raw materials Dighly active$ haAardous or toxic materials or products$ or otherwise incompatible materials are stored in such a way as to not pose a risk to other materials or products

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*roduction area&
C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

214 216

The operations carried out in any particular area are compatible$ so that the integrity of any product made in the area is not threatened 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 re)uire such facilities %'ote that campaign manufacture in the same facilities may be accepted provided that specific documented precautions are ta!en&+ @egistered veterinary medicinal products are not manufactured in the same areas as poisonous$ toxic or haAardous unregistered consumer products ;eterinary chemical products containing technical poisons are handled in segregated areas or separate buildings$ usually with e)uipment dedicated to this class of product %(owever common areas or equipment may be accepted provided that cross-contamination is controlled by scheduling or use of a validated cleaning procedure&. Premises are laid out in a way that allows the orderly and logical positioning of e)uipment 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 9here 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 )oints and do not shed particulate matter& ?nterior surfaces permit effective cleaning Eoins between walls and floors are easy to clean$ ade)uately sealed and where appropriate$ coved to form a smooth curve between the floor and wall 9ood or wood&based materials are avoided as a material of construction or support for e)uipment or materials in production areas$ especially where they may be wetted ?f used$ they are sealed with a coating that is resistant to chipping$ disinfectants and cleaning agents and that is easily cleaned The use of wood&based pallets is avoided in production areas where there is a risk of contamination of the product Pipe work$ light fittings$ ventilation points and other services are designed and located to avoid the creation of recesses that are difficult to clean !s far as practicable$ they are accessible from outside the manufacturing areas for maintenance purposes 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

217 215

218

22.

22221

222 223

224

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*roduction area& .cont1


C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

226

The arrangements for weighing or measuring raw materials minimise cross&contamination ( This may require the use of separate weighing or dispensing rooms designed and reserved for that us&e /ispensing rooms are not used as storage areas for starting and other materials 9here dust is generated (eg during sampling$ weighing$ mixing and processing operations$ or packaging of dry products)$ specific provisions are made and precautions taken$ to avoid cross&contamination (eg efficient dust extraction$ use of dedicated enclosed areas) and to facilitate cleaning Materials likely to shed fibres or other contaminants$ such as wooden pallets or fibreboard$ are not taken into areas where products or clean containers are exposed Production areas are well lit$ particularly where visual on&line controls are carried out

227

225 228

uality control area&


23. 23231 0uality control laboratories are separated from production areas This is particularly important with laboratories that handle microorganisms 0uality control laboratories are designed to suit the operations carried out in them :pace is sufficient to avoid mix& ups and cross&contamination There are ade)uate storage for samples and records :ensitive instruments are protected from adverse effects such as vibration$ electrical interference$ and humidity

Ancillary area&
232 233 :taff amenities$ including lunch rooms$ are separate from storage$ production and )uality control areas #lean and well&ventilated toilets and changing rooms are provided These are easily accessible and suitably isolated from any production$ )uality control or storage areas They are appropriate for the number of users and are maintained in a tidy and hygienic manner$ with an ade)uate supply of hot and cold water$ soap and hygienic hand&drying facilities ! 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 Maintenance workshops should$ as far as possible$ be separate from production areas 9henever parts or tools are stored in the production area$ they are kept in rooms or lockers reserved for that use

234 236

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Animal (ou&e&
C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

237

!reas in which animals are housed are ade)uately isolated from storage and processing areas$ with separate access for animals and separate air handling facilities

,ey ob&er-ation& and comment& .Comment on bot( po&iti-e and ne%ati-e a&pect& of Buildin%& and $round&+ Record e-idence &i%(ted and re-ie/ed0 &uc( a& 3O*&0 record& and ob&er-ation&0 particularly /it( re&pect to non-conformance1 +

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CORE ELEMENT 7 Manufacturin% principle&

E !"*MENT

*quipment used in the manufacture of veterinary chemical products must be suitable for its intended purpose and appropriately operated maintained and cleaned. *quipment must be correctly installed and operated in accordance with written instructions that are appropriate for the equipment. The design and layout of equipment must be such that" the ris! of manufacturing error is minimised effective cleaning and maintenance are possible in order to avoid cross-contamination of either intermediate materials or the finished product the buildup of dust or dirt and in general to avoid any adverse environmental effect on the quality of the product.

$eneral
C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

3.3.1 3.2

")uipment 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 ")uipment is used in accordance with written instructions that are appropriate to the e)uipment and consistent with any operating instructions issued by the e)uipment manufacturer Production e)uipment does not present any haAard 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 e)uipment that come into contact with materials being processed or the finished product are not reactive$ additive$ or absorptive to such an extent that product )uality is adversely affected ")uipment is uni)uely identified This identification is traceable to all records pertaining to the e)uipment ?f prone to failure or variance$ e)uipment used for critical steps in the manufacturing process is monitored by devices capable of recording the necessary operating parameters$ or is e)uipped with alarm devices to indicate malfunction ?f such devices are not practical$ the output is monitored to ensure early detection of variance Falances and other measuring e)uipment re)uired for production and )uality control operations are available and have an appropriate range and degree of precision ")uipment is properly positioned before use Bixed pipe&work is clearly labelled to indicate the contents and$ where applicable$ the direction of flow Pipes are ade)uately sloped for drainage and constructed without Gdead&legs= There are measures in place to ensure that materials transferred via pipelines are delivered to the correct destination /efective e)uipment is$ where possible$ removed from production and )uality control areas ?f it cannot be removed$ it is clearly labelled as defective

3.3 3.4

3.6 3.7

3.5

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E'uipment 'ualification and -alidation


C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

3.8

Hewly installed e)uipment that is critical to the manufacturing process is formally commissioned There are protocols for installation )ualification (?0) and operation )ualification (<0) of e)uipment These include the development and implementation of procedures for operation$ calibration$ maintenance and cleaning ")uipment that has been taken out of service$ modified or undergone major repairs is formally approved for re&entry into service

3-.

Maintenance
3-3-1 3-2 !ll e)uipment is properly maintained and records of this maintenance are kept ?n addition$ e)uipment is inspected for serviceability before any operation begins @epair and maintenance operations do not present any haAard to product )uality 9here continued maintenance of specific e)uipment is essential to product )uality$ documented maintenance procedures and records include the following% (a) (b) (c) details and fre)uency of preventive maintenance re)uirements' action to be taken if e)uipment maintenance re)uirements cannot be met' 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 e)uipment following the service

Calibration
3-3 "ach item of e)uipment used in manufacture or for )uality control purposes that measures$ or depends on$ a physical parameter (eg measuring$ weighing$ recording and control e)uipment)$ is calibrated at defined intervals$ in accordance with a written procedure That procedure describes the method and fre)uency of calibration or observation$ taking into account any statutory re)uirements$ as well as the action to be taken when results deviate from defined acceptance limits 9here appropriate$ verification checks are performed at a fre)uency consistent with the use of the e)uipment$ in accordance with a written procedure @ecords are kept of any calibrations$ verification checks or observations carried out on such e)uipment Those records contain sufficient information to show that the re)uired calibrations*observations have been carried out and provide details of any necessary corrective action taken

3-4 3-6

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Calibration .cont1
C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

3-7 3-5

")uipment calibration records show the actual results observed and the acceptance criteria 9here practicable$ each item re)uiring 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 wor!ing effectively&. There is evidence to demonstrate that the particular calibrating devices used are themselves accurate #ontractors who calibrate e)uipment are certified by a certification agency

3-8

Cleanin%
31. Manufacturing e)uipment is designed so that it can be easily and thoroughly cleaned 9here necessary$ it is easily dismantled for cleaning ?t is cleaned according to detailed written procedures$ and stored only in a clean$ dry environment @ecords are kept of e)uipment cleaning operations To facilitate cleaning$ e)uipment is mobile or clear of walls and floors 9here this is not practical$ e)uipment is sealed to the surfaces it touches Permanently fixed product and process&water pipelines have sanitary couplings and are sloped for drainage 9ashing and cleaning e)uipment is chosen and used in such a way that it is not a source of contamination 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 ")uipment is cleaned to the fre)uency and extent necessary to preserve product integrity ! cleaning record is kept either on the batch record or in an e)uipment log book ;alidation of cleaning procedures is considered where traces of ingredient may pose significant risk of contamination or toxicity in following product batches

31311 312 313 314 316

,ey ob&er-ation& and comment& .Comment on bot( po&iti-e and ne%ati-e a&pect& of E'uipment+ Record e-idence &i%(ted and re-ie/ed0 &uc( a& 3O*&0 record& and ob&er-ation&0 particularly /it( re&pect to non-conformance1+

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CORE ELEMENT 8 Manufacturin% principle&

DOC!MENTAT"ON

Manufacturers of veterinary chemical products must establish and maintain a system of documentation document control and record !eeping 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.

$eneral
C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

4.4.1

!ll processes and associated activities in the manufacture of veterinary chemical products are documented and the documents subjected to a system of document control Manufacturing documentation is designed$ prepared$ reviewed and distributed with care ?t complies with the relevant parts of product registration dossiers and registered particulars for the product and is regularly reviewed and kept up to date /ocuments are approved$ signed and dated by appropriate and authorised persons ?n 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. 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 /ocuments 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 /ocuments are not handwritten 9here data entries are handwritten or machine&printed$ they are clear$ legible and permanent :ufficient space is provided for such entries 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 ?t includes$ or is identifiable to$ the issuing premise and also includes the following information% (a) a uni)ue number identifying the document'

4.2

4.3 4.4

4.6 4.7

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Documentation 6 %eneral .cont1


C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

(b) (c) (d)


4.5 4.8

the version number and date it became effective' the page number of the total number of pages of the document on each page' provision for authorisation

@elevant documentation is available to cover manufacturing and associated activities at all locations @eproduced documents are clear and legible The reproduction of working documents from master documents (eg by photocopying or by computer printout)$ does not allow error to be introduced through the reproduction process ! designated competent person should initial each reproduced document before issue to signify that it is complete$ legible and appropriate !ny correction to a document should permit the reading of the original information #orrections are handwritten clearly and legibly in permanent ink$ and initialled and dated by an authorised person 9here appropriate$ the reason for the alteration is recorded 9here appropriate$ new or revised documents are introduced following a formal commissioning and training period

4-.

4--

Document control
4-1

The system of document control is documented That document definesw the procedures in place for% (a) (b) (c) (d) approval and regular review of documented procedures' distribution of documents' removal of obsolete documents from all points of issue and use' prevention of inadvertent use of superseded documents

4-2 4-3 4-4

! documented procedure is in place that defines the controls needed for the storage$ protection$ retrieval$ retention time and disposal of records 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 #hanges 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 subse)uent changes to procedures

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Document control .cont1


C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

4-6

9here key documents (eg master manufacturing formulae or master manufacturing instructions$ critical cleaning procedures) have been revised$ all associated or linked documents (eg batch manufacturing instructions$ batch documentation) are updated to reflect any relevant changes to the key documents$ or be otherwise linked to the revised documents

Record&
4-7 4-5 4-8 41.

@ecords are made or completed at the time each action is taken Manufacturing records are retained by the manufacturer for the period specified in the !gricultural and ;eterinary #hemicals #ode @egulations -884$ as cited below /ata 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 ?f 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 !ccess is restricted by passwords or other means :ee #hapter 6 (#omputer :ystems) of the GMP #ode for details Fatch records that are stored electronically are backed up by suitable means on a regular basis /ata are readily available throughout the period of retention #onsideration is given to storage of batch records and other critical records in a safe and secure environment

41411

+egulation ,-%.& A holder of a licence must make records showing: a! the materials used in the manufacture of the chemical "roducts, the su""lier and #uantities of the materials used and details of the tests "erformed on those materials$ and %! the "rocedures and controls em"loyed in the manufacture of the chemical "roducts, including the results of tests carried out during the "rocessing of the chemical "roducts$ and c! details of tests "erformed on the chemical "roducts and the results of those tests$ and d! the sta%ility studies if any! that &alidate the recommended shelf life and a""ro"riate storage conditions of the chemical "roducts' +egulation ,-%/& A holder of a licence must kee" at the "remises to which the licence relates: a! the records in su%regulation (!$ and %! if it is not unreasona%le in the circumstances ) a sam"le from each %atch of the finished "roducts$ for at least *2 months after the e+"iry date of the "roducts to which they relate or, if there is no e+"iry date, for at least , years after the date on which the manufacture of the "roducts was com"leted'

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Document& re'uired9
3pecification&
C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

412

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 9here appropriate$ they are also available for intermediate or bulk products :pecifications for starting and primary or printed packaging materials include$ where applicable% (a) a description of the materials$ including% (i) (ii) (iii) (iv) (v) (b) (c) (d) (e) (f) the designated name and the internal code reference' reference$ if any$ to a pharmacopoeial monograph$ or any other document on which the specification is based' the approved source of any active material' the preferred suppliers' and$ if relevant$ the original producer of the materials' a specimen of printed materials'

413

directions for sampling and testing$ or reference to procedures' )ualitative and )uantitative re)uirements with acceptance limits' storage conditions and precautions' the maximum period of storage before re&examination' any relevant safe handling instructions

414

9here 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 :pecifications 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

416

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3pecification& .cont1
C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

417

:pecifications for finished products include% (a) (b) (c) (d) the designated name of the product and the code reference where applicable' a description of the pharmaceutical form and package details' the )ualitative and )uantitative re)uirements$ such as visual$ organoleptic$ physical$ chemical and microbiological$ with the acceptance limits' the storage conditions$ shelf life and any special handling precautions$ where applicable

Material& control .&tore& receipt0 &tora%e and di&po&al1


415 418

There are written procedures and records for the receipt of each delivery of each starting material$ including immediate containers and printed packaging material The records of receipt include% (a) (b) (c) (d) (e) (f) (g) (h) the name of the material on the delivery note and the containers' the Gin&house= name and*or code of material if different' date of receipt' supplierIs name and$ if possible$ manufacturerIs name' original manufacturerIs batch or reference number' total )uantity$ and number of containers received' the uni)ue identifying number (J?H) assigned by the licensed manufacturer after receipt' any relevant comment (eg state of the containers)

42.

The records also include confirmation that% (a) (b) (c) (d) the goods have come from an approved supplier or$ if not$ an explanation why' the nature and )uantity of goods supplied is consistent with the order' the goods have been checked for damage' a valid certificate of analysis has been supplied for chemicals'

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Material& control .&tore& receipt0 &tora%e and di&po&al1 cont


C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

(e) (f) (g) (h) (i)


42-

at least a visual check for identity has been carried out' the material is consistent with documented specifications' each container is appropriately labelled and correctly identified' re)uired samples have been taken for testing and*or retention' the material has passed all re)uired )uality control tests

The records include the date of release by either 0uality #ontrol or an authorised$ competent person There are written procedures for the internal labelling (including status labelling to indicate whether under test$ )uarantined$ passed for use or rejected)$ )uarantine and storage of raw materials$ packaging materials and other materials$ as appropriate !ny special storage re)uirements (eg temperature) for individual materials are documented @ecords are kept to confirm that materials have been kept under appropriate storage conditions

421

Ma&ter manufacturin% formula0 ma&ter batc( record& and ma&ter manufacturin% proce&&in% in&truction&
422

Bormally 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 siAe to be manufactured They may be combined in one document The master manufacturing formula and master manufacturing instructions are prepared$ endorsed and dated by a competent person delegated by management ! 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 !ny amendments are checked by a second competent person The master manufacturing formula*master batch records include% (a) (b) (c) (d) the name of the product$ with a product reference code relating to its specification' a description of the pharmaceutical form (eg li)uid$ powder$ cream)$ strength or potency of the product$ and batch siAe' a list of all raw materials to be used$ with the amount of each ()uantity per unit dose and the )uantity per batch)$ using the designated name and provision for entry of the manufacturer=s J?H' a statement of the percentage excess$ where a predetermined excess (overage) of any ingredient is used'

423

424

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Ma&ter manufacturin% formula0 ma&ter batc( record& and ma&ter manufacturin% proce&&in% in&truction& .cont1
C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

(e) (f)

provision for making any adjustments for potency$ moisture etc' mention are made of any substance that may disappear in the course of processing' provision for entry of the expected final yield$ with the acceptable limits and of relevant intermediate yields$ where applicable

9here practicable$ batch siAes are standardised


426

The master manufacturing (or processing) instructions include% (a) (b) (c) (d) (e) (f) (g) (h) a statement of the processing location and the principal e)uipment to be used' the methods$ or reference to the methods$ to be used for preparing the critical e)uipment (eg cleaning$ assembling$ calibrating$ sterilising)' detailed stepwise processing instructions (eg checks on materials$ pre&treatments$ se)uence for adding materials$ mixing times$ temperatures) with provision to record relevant data$ such as time$ pD$ temperature' the instructions for any in&process controls$ with their limits' where necessary$ the re)uirements for bulk storage of the products$ including the container$ labelling and special storage conditions and*or time limits$ where applicable' any special precautions to be observed with regard to product )uality and personal safety (eg scheduling to prevent cross&contamination$ clothing re)uirements$ directions for dealing with spills$ if relevant)' provision for operator initials or signatures at suitable stages' a summary of all necessary )uality control tests and analyses$ and at what stage they are to be carried out

Ma&ter pac)a%in% and labellin% in&truction&


427 425

There are formally authorised master packaging and labelling instructions for each product pack siAe and type These may be combined with manufacturing records in one document The master packaging and labelling instructions are prepared$ endorsed and dated by an authorised person !n authorised second person checks$ endorses and dates the instructions$ where possible ?nstructions are kept up to date at all times and reviewed at intervals of no longer than three years !ny amendments are checked by an authorised second person The master packaging and labelling instructions include$ or have a reference to$ the following%

428

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Ma&ter pac)a%in% and labellin% in&truction& .cont1


C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

(a)

name of the product'

(b) description of its pharmaceutical form$ and strength$ where applicable' (c) (d) the pack siAe$ expressed in terms of the number$ weight or volume of the product in the final container' a complete list of all the packaging materials re)uired for a standardised batch siAe and$ where re)uired$ an actual batch siAe$ including )uantities$ siAes and types$ with the code or reference number relating to the specifications of each packaging material' where appropriate$ an example or reproduction of the relevant printed packaging materials or labels$ or the !P;M! label approval number(s)' special precautions to be observed$ including a careful examination of the area and e)uipment$ in order to ascertain the line clearance before operations begin' any relevant scheduling and*or special cleaning instructions' and any relevant safety precautions' a description of the packaging operation$ including any significant subsidiary operations$ and e)uipment to be used' details of in&process controls$ with instructions for sampling and acceptance limits' the approved shelf life' provision for calculation of batch yield' provision for label reconciliation

(e) (f)

(g) (h) (i) (j) (k)

Batc( manufacturin%:proce&&in% record&


43.

! batch manufacturing record is kept for each batch processed ?t is based on the current$ approved master manufacturing formula*master batch record and manufacturing instructions and may be a photocopy of the master documents or a specially designed computer print&out The method of preparation of such records is designed to avoid transcription errors The record carries the number of the batch being manufactured "ach batch of product is provided with a uni)ue identifiable batch number$ as specified in the !gvet #odes @egulations /uring processing$ information is recorded at the time each action is taken and$ after completion$ the record is dated and signed showing agreement by the person responsible for the processing operations The information recorded includes% (a) dates and times of commencement of significant intermediate stages and of completion of production'
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Batc( manufacturin%:proce&&in% record& .cont1


C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

(b) (c) (d)

name of the person responsible for each stage of production' initials of the operator of each significant step of production and$ where appropriate$ of the person who checked each of these operations (eg weighing)' the J?H$ as well as the )uantity of each starting material actually weighed (including the batch number and amount of any recovered or reprocessed material added)'

(e) a record to confirm that the e)uipment and work station are clear of previous products$ documents or materials not re)uired for the planned process$ and that e)uipment is clean and suitable for use' (f) (g) (h) (i) any relevant processing operation or event and major e)uipment used' a record of the in&process controls$ the initials of the person(s) carrying them out$ and the results obtained' the final product yield$ as well as yields obtained at pertinent stages of manufacture' notes on special problems$ including details$ with signed authorisation$ for any planned deviation from the manufacturing formula and processing instructions and authorisation for processing to continue in the event of unplanned deviations

Batc( pac)a%in% record&


431

! batch packaging record is kept for each batch or part batch processed ?t is based on the master packaging instructions and may be a photocopy of the master documents or a specially designed computer print&out The method of preparation of such records is designed to avoid transcription errors The record carries the batch number and the )uantity of bulk product to be packed$ as well as the estimated )uantity of finished product that will be obtained Fefore any packaging operation begins$ there are recorded checks that the e)uipment and workstation are clear of previous products$ documents or materials not re)uired for the planned packaging operations$ and that e)uipment is clean and suitable for use (line clearance) The following information are entered at the time each action is taken and$ after completion$ the record is dated and signed showing agreement by the person(s) responsible for the packaging operations% (a) (b) the date and time of the packaging operation' the name of the responsible person carrying out the packaging operation' and the initials of the operators of significant steps'

432

433

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Batc( pac)a%in% record& .cont1


C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

(d)

a record to show that all packaging materials and labels have been assembled before starting and checked for identity and conformity with the packaging instructions and that the labels carry$ or are to be printed with$ the correct batch number and expiry date' details of the packaging operations carried out$ including references to e)uipment and the packaging lines used' notes on any special problems or unusual events$ including details with signed authorisation for any deviation from the master packaging instructions' the signature of the person responsible for the operation confirming that the operation has been carried out in accordance with the packaging and labelling instructions' where practicable$ a sample of the label used$ showing the added batch number and expiry date$ and any other overprinting$ as well as samples of any other pre&printed packaging materials used' the )uantities and J?Hs*batch numbers of all printed packaging materials and bulk product issued$ used$ destroyed or returned to stock and the )uantities of obtained product' results for batch yield from the bulk supplied to be packed and$ unless otherwise justified$ for reconciliation of labels and pre&printed packaging materials 9here practicable$ any part&batch packed are subject to yield and reconciliation controls

(e) (f) (g) (h) (i) (j)

9here product is filled into unlabelled containers for later labelling$ special precautions are taken to maintain the identity of the product during storage

uality control &amplin% and te&tin%


434

There are written procedures for sampling and testing as specified in #hapter 5 of the GMP #ode

Relea&e:rejection and di&tribution of fini&(ed product


436 437

9ritten release and rejection procedures are available for materials and products$ and in particular for the release for supply of the finished product by the authorised person(s) designated for the purpose Fatch records show the name of the person responsible for releasing the product for supply$ and confirm$ by way of that person=s signature$ that% (a) all manufacturing documents have been reviewed'

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Relea&e:rejection and di&tribution of fini&(ed product .cont1


C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

(b) (c) (d) (e)


435 438

all entries are complete' there are no unexplained or unresolved deviations' the product meets all specifications' a final packed item has been visually examined

9here finished product has been rejected$ the batch records include a note as to the reason and confirm that the batch has been status&labelled and appropriately )uarantined and*or disposed of @ecords are maintained of the distribution of each batch of a product$ in order to facilitate a recall

Complaint&0 recall& and return&


44.

@ecords of complaints$ recalls and returned products are retained for an appropriate period$ to be defined by the manufacturer

Computer record&
44-

9here computer systems are used to store critical manufacturing information or control manufacturing processes$ records are maintained as re)uired by #hapter 6 of the GMP #ode

Laboratory record&
441

@ecords maintained in )uality control laboratories meet the re)uirements of #hapter 5 of the GMP #ode

;alidation record&
442

@ecords are kept of all validation studies carried out ?n 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

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Ot(er record&
C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

443

There are written procedures and records of actions taken or conclusions reached$ where appropriate$ for% (a) (b) (c) (d) (e) (f) 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)' general maintenance$ cleaning and sanitisation (cleaning and sanitising instructions should include the name and strength of any cleaning*sanitising agent used)' e)uipment installation and assembly$ )ualification and calibration ()ualification and calibration records should show tolerance limits)' e)uipment maintenance$ cleaning and sanitisation (cleaning and sanitising instructions should include the name and strength of any cleaning*sanitising agent used)' personnel matters$ including medical checks$ training$ clothing and hygiene' environmental monitoring (including temperature and other controlled&environment monitoring devices)

444 446 447

#lear operating procedures and$ where appropriate$ specific cleaning instructions$ are available for major items of manufacturing and test e)uipment Cog books or e)uivalent records are kept for major or critical e)uipment$ to record any validations$ calibrations$ maintenance$ or repair operations$ including dates and the identity of people who carried out those operations Cog books or e)uivalent records also record$ in chronological order$ the use and cleaning of major or critical e)uipment and of the areas where the products have been processed

,ey ob&er-ation& and comment& .Comment on bot( po&iti-e and ne%ati-e a&pect& of Documentation and Record&+ Record e-idence &i%(ted and re-ie/ed0 &uc( a& 3O*& and record&0 particularly /it( re&pect to non-conformance1 +

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CORE ELEMENT < Manufacturin% principle&

COM*!TER 3#3TEM3

0here 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 sub)ect 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.

$eneral
C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

6.6.1

! written description of the system is available and kept up to date ?t describes the objectives of the system and how it interfaces with other systems and processes Fefore a system involving a computer is brought into use$ it is thoroughly tested and shown to be capable of achieving the intended outcomes ?f 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 e$tent of validation necessary will depend on a number of factors including the intended outcomes whether it is prospective or retrospective and whether novel elements are incorporated ?f software has been commissioned specifically for the manufacturer$ 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 )ualification ?f the software is Goff&the&shelf=$ but has been configured for the manufacturer=s use$ then installation )ualification and operational )ualification 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 )ualification shows how the system successfully handles instructions and data ?f Goff the shelf= software has been partly or fully customised$ its development is treated as in 6.2 above ?f the software is Goff&the&shelf= and has not been configured or customised for use$ then it is precisely defined and installation and performance )ualification are carried out to demonstrate that user re)uirements have been satisfied

6.2

6.3

6.4 6.6

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Computer &y&tem& 6 %eneral .cont1


C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

6.7

!lterations to a computer system are made only in accordance with a change control procedure$ which include provision for checking and approving the changes and$ to the appropriate extent$ performing operational and*or performance )ualification 9hen outside agencies provide a computer service$ there is a formal agreement that includes a clear statement of the responsibilities of that outside agency ! second authorised person verifies the entry of all critical data$ such as master formulae$ into a computer system The system is capable of providing printed copies of all stored data relevant to product )uality Printed matter produced by computer peripherals is clearly legible ! procedure is established to record and analyse errors and to enable corrective action to be taken The system records the identity of persons who enter or confirm critical data and is capable of creating a time&stamped record of such entries or confirmations and of all amendments /ata are entered only by authorised persons and there are methods of preventing unauthorised entry There is a defined procedure for the issue$ alteration or cancellation of authority to enter and amend data ?f the computer system is used for batch release$ the authority to release is clearly defined @ecords are backed up regularly and progressively$ and the backup is retained at a secure and remote location until the next backup is filed Permanent archived electronic records are transferred to new media at regular intervals to avoid loss There are contingency plans and recovery procedures for use in the event of a breakdown of the system This may be part of a broader disaster recovery plan

6.5 6.8 6-. 6-6-1 6-2 6-3 6-4

6-6

,ey ob&er-ation& and comment& .Comment on bot( po&iti-e and ne%ati-e a&pect& of Computer 3y&tem&+ Record e-idence &i%(ted and re-ie/ed0 &uc( a& 3O*& and record&0 particularly /it( re&pect to non-conformance1+

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CORE ELEMENT = Manufacturin% principle&

*ROD!CT"ON

Veterinary chemical products must be manufactured to specifications in accordance with manufacturing information supplied as part of their application for registration and1or 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. 0here 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.

$eneral
C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

7.-

"ach material used is consistent with documented specifications and the master manufacturing formula$ and each step of manufacture carried out (such as receipt and )uarantine$ )uality assurance of raw materials$ dispensing$ processing$ packaging$ labelling and )uality control procedures) is in accordance with documented procedures and the master manufacturing instructions Bor each batch of product made$ records are kept of all materials used and of all critical steps and control procedures carried out !ll 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 The manufacturing process are periodically monitored at all critical stages to ensure both the reliability of the manufacturing process and product )uality$ including microbial testing if relevant The identity and where relevant$ the status of every material$ including waste$ is clearly shown on the outside of its container

7.1 7.2 7.3 7.4

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Material& control .includin% &tora%e1 .a1 $eneral


C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

7.6 7.7 7.5 7.8

@ecords are kept of all incoming materials received in the store (whether raw materials$ intermediate or bulk products or finished products) !ll incoming raw materials and packaging materials are checked to ensure that the consignment corresponds with the order #ontainers are cleaned where necessary and clearly labelled /amage to containers and any other problem that might adversely affect the )uality of a material is investigated$ recorded and reported to 0uality #ontrol ?ncoming raw materials and finished products are physically or administratively )uarantined immediately after receipt or processing until they have been released for use or distribution ?f physically )uarantined$ designated )uarantine areas are available for this purpose Materials received as intermediate or bulk products are handled on receipt as though they were raw materials !ll materials and products are stored under conditions that will minimise deterioration and are stored in an orderly fashion to permit batch segregation and stock rotation

7-. 7--

.b1
7-1 7-2 7-3

Receipt0 &tora%e and 'uality a&&urance of ra/ material&


@aw materials are purchased only from approved suppliers named in the relevant specification "ach delivery of starting material is given a uni)ue identifying number (J?H) ?f one delivery of material is made up of different batches$ each batch is considered as separate for sampling$ testing and release and given a separate J?H @aw materials are appropriately labelled on receipt with at least the following information% (a) (b) (c) (d) the designated name of the starting material and the internal reference code where applicable (each starting material is identified by and used under one name only)' a number (J?H) given at receipt' the status of the contents (eg )uarantined$ on test$ released$ rejected)' where appropriate$ an expiry date or a date beyond which retesting is necessary

'ote that when computerised storage systems are used all the above information need not necessarily be specified in te$t on the label.

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C(ec) *oint No+

Receipt0 &tora%e and 'uality a&&urance of ra/ material& .cont1


C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

7-4 7-6 7-7 7-5

!s soon as possible after receipt$ each starting material is assessed$ in accordance with a written procedure$ for its suitability for use$ as set out in #hapter 4 of the GMP #ode ! stock rotation system is implemented to ensure that raw materials are used by the nominated expiry*retest date There are appropriate procedures or measures to ensure that the identity and status of all containers of raw materials can be recognised from their labelling at all times #ontainers from which samples have been drawn are identified The handling and treatment of animals used for production and testing purposes complies with all the relevant animal welfare guidelines !nimals used for production purposes or for testing components$ materials or products are$ where appropriate$ be )uarantined before use They are maintained and controlled and where necessary subjected to testing$ to assure that they meet specifications and are suitable for the intended use They are identified$ and ade)uate records are maintained showing the history of their use

.c1
7-8 71. 71711 712

Receipt0 &tora%e and 'uality a&&urance of pac)a%in% material&


Jpon receipt$ packaging materials$ including printed labels$ are )uarantined until checked against specifications and approved "ach delivery or batch of printed or primary packaging material received is given a specific reference number or identification mark Pre&printed labels are not overprinted with a different name$ dosage$ formula or strength of the product Cabelling materials are only issued for use by authorised personnel following an approved and documented procedure :tocks of labels and pre&printed packaging materials are checked annually and outdated or obsolete material destroyed This disposal is recorded

Cro&&-contamination control
713 #ross&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& '

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Cro&&-contamination control .cont1


C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

(b) (c) (d) (e) (f) (g) (h) (i) 714

ade)uately isolating plant and*or e)uipment by a suitable distance' production on a campaign basis$ followed by appropriate and validated cleaning$ or scheduling the manufacture of different products in an appropriate se)uence' providing effective air*dust extraction systems and*or airlocks' keeping lids on mixing vessels' avoiding recirculation or re&entry of untreated or insufficiently treated air' keeping protective clothing inside areas where products with special risk of cross&contamination are processed' using effective and validated cleaning*decontamination procedures$ and using cleaning status labels' using Gclosed= production systems

9here cross&contamination has the potential to cause a haAard to the treated animal$ the effectiveness of cross& contamination control measures is monitored periodically according to set procedures

*roce&& -alidation
716 717 #ritical 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 9hen 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 e)uipment specified$ is shown to yield a product consistently of the re)uired )uality ;alidation studies are conducted in accordance with defined procedures They include the most challenging of any permitted ranges in process variables @esults and conclusions are recorded as technical reports

715

*roduction procedure
.a1
718 72.

Di&pen&in% of ra/ material&


The raw materials used for a particular product conform to the master manufacturing formula Ho substitution is allowed unless the change is authorised in writing by an authorised person. <nly raw materials that have been released for use and which are within their shelf life$ are used

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.a1
C(ec) *oint No+

Di&pen&in% of ra/ material& .cont1


C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

72721 722

@aw materials are dispensed only by designated persons$ following a written procedure #orrect materials are accurately weighed or measured into clean and properly labelled containers The dispensing operation is supervised or verified to the extent necessary to ensure the accuracy of the weight*volume and the identity of the materials and all checks are recorded Materials dispensed for each batch are kept together$ isolated from other materials and be conspicuously labelled with the product batch number

.b1
723

*roce&&in% operation&
Fefore any processing operation is started$ steps are taken to ensure that the work area and e)uipment are clean$ suitable for use and free from any raw materials$ products$ product residues or documents not re)uired for the current operation The product is manufactured in full accordance with authorised batch manufacturing instructions !ny variation from those instructions is authorised in writing by an authorised person ?ntermediate preparations$ such as solutions used for pD adjustments or coating solutions$ are prepared following the same system of master formulae and processing instructions and their batch numbers are carried forward onto the documents for the finished products in which they are used 9here operations on different products are carried out simultaneously or consecutively in the same room$ and where this is a product )uality or safety issue$ there are measures in place to prevent mix&up and*or cross&contamination !t every stage of processing$ products and materials are protected from microbial and other contamination 9hen working with dry materials and products$ precautions are taken to minimise the generation and dissemination of dust This applies particularly to the handling of highly active or sensitising materials !t all times during processing$ all materials$ bulk containers$ major items of e)uipment and$ where appropriate$ rooms used$ are labelled or otherwise identified with the name of the product or material being processed$ its strength (where applicable) and batch number 9here applicable$ the label also mentions the stage of production Cabels applied to containers$ e)uipment or premises are clear$ legible$ easily understood and in the manufacturer=s agreed format 2olours may be used in association with wording to indicate status

724 726

727 725 728 73.

73-

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C(ec) *oint No+

*roce&&in% operation& .cont1


C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

731 732 733 734

#hecks are carried out to ensure that transfer lines and other pieces of e)uipment used for the transportation of products from one area to another are clean before use and are connected in a correct manner !s far as possible$ deviations from standard procedures are avoided 9here deviations occur$ they are approved in writing by an authorised person The production of incompatible products is avoided in areas and e)uipment destined for the production of veterinary chemical products$ unless precautions are taken to ensure the integrity of these veterinary chemical products !ll intermediate yields and the final product yield are checked and )uantities reconciled against the theoretical or expected values by a competent person !ny discrepancy that exceeds acceptable limits is recorded on the batch records and investigated$ and the batch )uarantined until its status has been determined

.c1
736 737 735 738

"ntermediate and bul) product&


?ntermediate and finished products awaiting release by 0uality #ontrol are segregated physically$ or by an e)uivalent computer system$ from other stock ?ntermediate and bulk products are stored under appropriate conditions that are clearly defined and documented. Materials are transported between premises or buildings in a manner that ensures the integrity and status of the material /elays in completion of the manufacturing process are kept to a minimum The maximum holding time for intermediate and bulk materials is clearly defined and justified

.d1
74. 74741

*roce&& /ater
The )uality of water re)uired (potable or processed) is specified and consistent with approved registration details 9here water is treated for use as an ingredient$ a specification for this process water is developed$ based on sound physical$ chemical and microbiological principles @aw water is purified before use to meet this specification 9here process water is used$ a water )uality manual is prepared This document may be part of the manufacturer=s )uality manual and should include%

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.d1
C(ec) *oint No+

*roce&& /ater .cont1


C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

(a) a drawing of the purification$ storage and (where applicable) reticulation system$ showing all pipelines$ valves$ sample points$ breather points$ drain points$ couplings$ instrumentation$ pipe slopes$ flow rates and velocities of water flow' (b) both a brief description of and a full specification for each element in the system$ including manufacturers= recommended flow rates' (c) standard procedures for use$ including start&up$ shutdown$ backwashing$ regeneration$ sanitising and filter maintenance and testing' (d) a log of system changes$ routine and non&routine maintenance (unless routine maintenance is logged elsewhere and the log is readily available)$ investigations$ corrective action and validation studies' (e) chemical and microbiological specifications$ including resample$ action and shutdown limits' (f) sampling instructions and testing procedures$ including validation of procedures'

(g) results of tests$ including graphical presentations' (h) the positions of persons responsible for the operation and maintenance of the system and their deputies' (i) 742 periodic reviews$ conducted at least once per year

Process water is tested at a fre)uency consistent with the history of successful control :ampling procedures include Gworst case= sample points and production conditions The sample siAe tested is sufficient to demonstrate process control Microorganisms recovered from total counts are occasionally separately identified !typical results are investigated

743

*rimary .fillin%1 and &econdary pac)a%in% operation&


744 Programs for packaging operations are devised to minimise the risk of cross&contamination$ mix&ups or substitutions /ifferent products are not packaged in close proximity unless there is physical segregation or the distance is great enough to avoid a mix&up Fefore packaging operations are begun$ a line clearance is undertaken to ensure that the work area$ packaging lines$ printing machines and other e)uipment are clean and free from any products$ materials or documents previously used$ if these are not re)uired for the current operation

746

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*rimary .fillin%1 and &econdary pac)a%in% operation& .cont1


C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

747 745 748 76. 76761 762 763 764

The name and batch number of the product being handled are displayed at each packaging station or line !ll products and packaging materials to be used are checked on delivery to the packaging department for )uantity$ identity and conformity with the packaging instructions #ontainers are clean before filling !ttention is given to avoiding$ and if necessary removing$ any contaminants such as glass fragments and metal particles Billing and sealing are followed as )uickly as possible by labelling 9here this is not the case$ appropriate procedures are applied to ensure that no mix&ups or mislabelling occur The correct printing of code numbers or expiry dates$ etc$ done either separately or in the course of the packaging$ is checked and recorded Printing by hand is re&checked at regular intervals :pecial care is taken when using cut labels and when over&printing takes place off&line Printed and embossed information on packaging materials is distinct and resistant to fading or erasing #hecks are made to ensure that any electronic code readers$ label counters or similar devices are operating correctly <n&line control of the product during packaging includes checking at least the following% (a) (b) (c) (d) (e) general appearance of the packages' whether the packages are complete' whether the correct products and packaging materials are used' whether any over&printing$ such as batch numbering and expiry dating$ is correct' correct functioning of line monitors

:amples taken away from the packaging line are not returned 766 Products that have been involved in an unusual event (eg a mid&process breakdown in production or storage conditions) are only reintroduced into the process after special inspection$ investigation and approval by authorised personnel /etailed records are kept of this operation <n completion of the packaging operation$ yields are determined and reconciliation conducted !cceptable limits are established !ny significant or unusual discrepancy is investigated and satisfactorily accounted for before release Jpon completion of a packaging operation$ any unused batch&coded packaging materials is destroyed and the destruction recorded Jnused printed material is re&inspected before being returned to stock

767 765

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Relea&e of fini&(ed product&


C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

768 77. 77-

Binished products are held in )uarantine$ under conditions established by the manufacturer$ until their final release !ll product batches are sampled for )uality control and are not released for supply until all specified tests are completed !fter release$ finished products still under the control of the manufacturer$ are stored under conditions consistent with the approved product label

Re&idual0 rejected0 reco-ered and returned material&


771 Product residues are not be incorporated into subse)uent batches of product on a routine basis$ except where this is provided for in the master formula or processing instructions and where limits are prescribed for the proportion of residue ?n addition$ a standard operating procedure should specify at least% (a) (b) (c) (d) (e) 772 limits on the age and total )uality of residue that may be accumulated' limits on the number of batches of residue that may be incorporated in a single batch of product' limits on the total )uantity or proportion of residue that may be incorporated in a single batch of product' a procedure for use and*or disposal that will facilitate overall reconciliation' any necessary testing or approval

@ejected materials and products are clearly marked as such and stored separately in clearly identified restricted ()uarantine) areas They are either returned to the suppliers or$ where appropriate$ reprocessed or destroyed !ction taken is approved and recorded by authorised personnel @ecovery of all or part of earlier batches (that conform to the re)uired )uality)$ by incorporation into a batch of the same product at a defined stage of manufacture$ is authorised beforehand This recovery is carried out in accordance with a defined procedure after evaluation of the risks involved$ including any possible effect on shelf life The recovery is recorded Binished product returned from the manufacturer=s own stores or warehouse (eg because of soiled or damaged labels or outer packaging) is only relabelled$ or bulked for repacking when there is no risk to product )uality and the operation is specifically authorised and documented ?f such a product is relabelled$ the operation is regarded as a formal packaging operation ?f bulked$ the operation is regarded as a formal processing operation

773

774

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Re&idual0 rejected0 reco-ered and returned material& .cont1


C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

776

Products returned from the market$ which have left the control of the manufacturer$ are destroyed$ unless without doubt their )uality is satisfactory They are considered for re&sale$ relabelling or recovery with a subse)uent batch$ only after they have been critically assessed by 0uality #ontrol in accordance with a written procedure The nature of the product$ any special storage conditions that it re)uires$ its condition and history$ and the time elapsed since it was issued are all taken into account in this assessment There is no adverse effect on the shelf life of the product batch 9here any doubt arises over the )uality of the product$ it is considered un&suitable for re&issue or re&use$ although basic chemical reprocessing to recover active ingredients may be possible !ny action taken is appropriately recorded The need for additional testing of any finished product that has been reprocessed$ or into which a recovered product has been incorporated$ is considered by 0uality #ontrol ! suffix or batch number is used to distinguish any bulked or re&labelled material

777 775

,ey ob&er-ation& and comment& .Comment on bot( po&iti-e and ne%ati-e a&pect& of *roduction *rocedure&+ Record e-idence &i%(ted and re-ie/ed0 &uc( a& 3O*&0 record& and ob&er-ation&0 particularly /it( re&pect to non-conformance1 +

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CORE ELEMENT > Manufacturin% principle&

!AL"T# CONTROL

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 manufacturer3s 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.

$eneral
C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

5.-

The manufacturer has an identifiable )uality control function This function is independent from other functions and under the authority of a person (with appropriate )ualifications and experience)$ who has access to one or more control laboratories !de)uate resources are available to ensure that all the )uality control arrangements are effectively and reliably carried out 9here practicable$ a )uality control laboratory is available and ade)uately staffed and e)uipped for the performance of all )uality control tests re)uired before$ during and after manufacture 9here there is no in&house facility$ or the in& house facility does not have the capability of doing all re)uired )uality tests$ satisfactory alternative arrangements for the re)uired )uality control testing exist The principal duties of the head of 0uality #ontrol are summarised in #hapter 1 (clause 1-.) of the GMP #ode 0uality #ontrol also has other duties$ which may include% (a) (b) (c) (d) (e) (f) establishing ade)uate )uality control specifications for all materials at all stages of manufacture and for the finished product' establishing$ documenting$ validating and implementing all )uality control test procedures' assessing and releasing*rejecting starting and intermediate materials for each batch' assessing and releasing*rejecting each batch of finished product for supply' keeping reference*retention samples of materials and products' ensuring the correct labelling of containers of materials and products'

5.1

5.2

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uality control 6 %eneral .cont1


C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

(g) (h) (i) (j) (k) (l)

monitoring the suitability of packaging materials' monitoring the stability of the products$ the suitability of expiry dates and product storage conditions' participating in the investigation of complaints related to the )uality of the product' monitoring environmental control of )uality control laboratories and test animal houses as appropriate' reviewing trends in analytical results or yields' establishing or approving procedures for animal )uarantine$ animal testing and the recovery of biological material from animals for use in analysis$ testing or production

!ll these operations are carried out in accordance with written procedures and recorded 5.3 !nalytical laboratories and animal testing facilities follow the principles of good laboratory practices (GCP) 9ritten procedures are established for at least the following% (a) (b) (c) (d) (e) (f) 5.4 cleaning of )uality control areas and e)uipment' preparation of materials and reagents' maintenance of reference substances' calibration and maintenance of )uality control e)uipment' dealing with out&of&specification results' reviewing analytical performance

0uality #ontrol personnel have access to production areas for sampling and investigation as appropriate They are empowered to take samples from any stage of the manufacturing process or from finished products at any time$ and take and retain samples$ using documented procedures$ as re)uired in clauses 5-2 ( 512 0uality #ontrol receives prompt information on any proposed changes or modification to material sourcing$ specification$ production procedures or written instructions 9here any )uality control testing is contracted to an external laboratory% (a) (b) the records of this testing indicate the source of the test results (see #hapter 8 of the GMP #ode)' the laboratory complies with !: ?:<*?"# -7.14$ or with any subse)uent amendment'

5.6 5.7

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uality control 6 %eneral .cont1


C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

(c) 5.5

the laboratory$ if located in !ustralia$ is appropriately licensed by !P;M! to test veterinary chemical products in the manner re)uired.

!nimals used for testing components and products are handled in the same way as those used in the manufacturing process (see clause 7-5$ #hapter 7 of the GMP #ode)

Documentation
5.8 Caboratory documentation follows the general principles given in #hapter 4 G/ocumentation= of the GMP #ode The following information is either prepared by$ or readily available to$ 0uality #ontrol% (a) specifications'

(b) sampling procedures' (c) (d) (e) (f) (g) 5-. 5-5-1 testing procedures and records (including analytical worksheets and*or laboratory notebooks)' analytical reports and*or certificates' data from environmental monitoring$ where re)uired' validation records of test methods$ where applicable' procedures for and records of$ the calibration of instruments and maintenance of e)uipment

!ny )uality control documentation relating to a batch record is retained for the period defined in clauses 4-7&411$ in #hapter 4 of the GMP #ode @ecords of analytical test results$ yields and environmental controls are kept in a manner permitting trend evaluation ?n 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

3amplin%
.a1
5-2

3amplin% plan&
:ampling plans for starting materials (excluding packaging materials)% (a)K differentiate between certified$ approved and other suppliers$ including unknown suppliers$ as appropriate'

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.a1
C(ec) *oint No+

3amplin% plan& .cont1


C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

(b) differentiate between starting materials that do not bear a manufacturer=s batch number and those that do' (c)K take account of the nature of each material$ for example its potency and whether its place and method of manufacture may ensure against mix&up or even make mix&up impossible' (d) take account of the intended use of the material (eg whether it is for injection)' (e)K differentiate between materials that may be expected to vary from container to container (eg by separation or moisture uptake) and those that may not' (f)K prescribe the action to be taken where a delivery from a certified or approved supplier has failed' (g) prescribe an increased sampling rate for damaged containers or for lots that do not appear to be homogenous' (h) specify the extent of pooling of samples destined for tests other than identification' (i) 5-3 re)uire the sampling officer or analyst to initially examine each sample for homogeneity$ evidence of deterioration or other visible defect

:ampling plans for packaging materials should take into account% (a) (b) (c) the items shown as (K) listed in #lause 5-2 for starting materials' the need to check the identity of each container or reel of labels and pre&printed packaging materials' the number of samples needed to reach a valid decision to approve or reject a delivery in relation to )uality& related defects

.b1
5-4

3amplin% *rocedure&
:amples are taken in accordance with approved written procedures that describe% (a) (b) (c) (d) (e) the method of sampling' the e)uipment to be used' the amount of the sample to be taken' instructions for any re)uired subdivision or pooling of samples' the type and condition of the sample container to be used'

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C(ec) *oint No+

3amplin% *rocedure& .cont1


C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

(f) (g) (h) (i) 5-6 5-7 5-5 5-8

the identification of containers sampled' any special precautions to be observed$ especially with regard to the sampling of sterile or noxious materials' the storage conditions' instructions for the cleaning and storage of sampling e)uipment

The sampling procedure is justified$ taking into consideration the nature of the material or the method of manufacture of the product being sampled :ample containers bear a label indicating the contents$ the batch number$ the date of sampling and the containers from which samples have been drawn !ll samples taken for )uality control purposes are taken by 0uality #ontrol personnel$ except samples for in&process control$ which may be taken by authorised production staff !ll the in&process controls$ including those made in the production area by production personnel$ are performed according to methods approved by 0uality #ontrol and the results are recorded

.c1
51.

Retention &ample&
0uality #ontrol take and retain samples of% (a) (b) at least each batch of active starting material' each batch of finished product

51-

@etention samples of materials and products are of a siAe sufficient to permit at least a full re&examination ?n the case of active raw materials$ the )uantity taken is at least twice the )uantity re)uired to establish identity and purity ?n the case of finished products$ the number of units retained will depend on the product but are ade)uate to permit re& examination at a suitable time and investigation of possible complaints @etention samples from each batch of finished products are retained for the period specified in the !gvet #ode @egulations (see #hapter 4' G@ecords= of the GMP #ode) 9here practicable$ these samples are kept in their final packaging 9here the finished product samples are not stored in their final packaging$ the packaging chosen is of the same materials as the manufactured product @etention samples are stored under the recommended conditions

511

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.c1
C(ec) *oint No+

Retention &ample& .cont1


C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

512

:amples of starting materials (other than solvents$ gases and water) are retained for at least two years after the release of the product$ if their stability allows %'ote" This period may be shortened if their shelf life as mentioned in the relevant specification is shorter&

*roduct relea&e
513 Products are released in accordance with the procedures specified in #hapter 4 in the GMP #ode

,ey ob&er-ation& and comment& .Comment on bot( po&iti-e and ne%ati-e a&pect& of uality Control+ Record e-idence &i%(ted and re-ie/ed0 &uc( a& 3O*& and record&0 ob&er-ation&0 etc0 particularly /it( re&pect to non-conformance1 +

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CORE ELEMENT ? Manufacturin% principle&

CONTRACT MAN!@ACT!RE

0here 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 4GMP Agreement3 that clearly specifies each party3s 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. 0here a contractor is authorised to manufacture under the licence of another manufacturer the licence holder must e$ert direct control and oversight of the quality management of the contracted step.

$eneral
C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

8.8.1

#ontracted 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 9hen the manufacturer (Gcontract giver=) contracts all or some of the steps of manufacture to another manufacturer (Gcontract acceptor=)$ a written agreement (usually referred to as a GGMP !greement= or G:pecification of GMP @esponsibilities=) is drawn up that clearly defines the steps of manufacture$ or scope of any analytical work$ to be carried out ?t also defines the GMP responsibilities of each party for each aspect of the work !ll GMP !greements are kept up to date #ontract manufacture is undertaken only by a manufacturer who is the holder of an !P;M! Manufacturer=s Cicence$ unless the work undertaken by the contract acceptor falls within the scope of the contract giver=s licence as specified in !gricultural and ;eterinary #hemicals #ode @egulations -884$ cited below

8.2

+egulation /5A" A "erson who "erforms only a single ste" in the manufacture of a "roduct is an e+em"t "erson in relation to the manufacture if: a! the ste" consists only of: i! "ackaging or la%elling, or %oth "ackaging and la%elling, the "roduct$ or ii! analysing or testing the "roduct$ and %! either: i! the licence that authorises the manufacture of the "roduct %eing a licence held %y another "erson! "ermits the first-mentioned "erson to "erform the ste" for the "roduct$ or ii! the ste" consists only of a""lying a la%el that contains only a name and address, or the registration num%er of the "roduct, or %oth, to a "ackage, or "ackages of the "roduct'

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T(e $M* A%reement


C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

8.3

The GMP !greement clearly describes who is responsible for purchasing materials$ testing and releasing materials and undertaking production and )uality controls$ including in&process controls$ sampling$ analysis$ release for supply and the storage of records and retention samples The !greement permits the contract giver$ an agreed third party or an !P;M!&authorised GMP auditor to visit the facilities of the contract acceptor for auditing purposes The agreement also re)uires the contract giver to provide$ for this purpose$ access to details of relevant analytical methodology and validation studies$ or manufacturing procedures$ )uality control tests and manufacturing records Technical aspects of the contract are drawn up by competent persons with knowledge of veterinary chemical manufacture$ analysis and*or GMP$ as is appropriate !ll arrangements for manufacture and analysis are in accordance with the appropriate product registration and be agreed to by both parties

8.4

8.6

T(e contract %i-er


8.7 8.5 <nly !P;M!&authorised manufacturers are selected to carry out the specified steps of contract manufacture The contract giver provides the contract acceptor with all the information necessary to carry out the contracted operations correctly in accordance with registered particulars and any other legal re)uirements The contract giver also ensures that the contract acceptor is fully aware of any aspects of the product or the work which might pose a haAard to the contract acceptor=s premises$ e)uipment$ personnel$ or other materials or products used or made on the premises The contract giver accepts responsibility for% (a) (b) (c) assessing the competence of the contract acceptor to successfully carry out the re)uired work' ensuring that all arrangements for steps of manufacture$ including any proposed changes of a technical nature$ are in accordance with the registration particulars for the product concerned' ensuring that all materials or processed products delivered to them by the contract acceptor comply with their specifications$ and that they have been released by a competent authorised person

8.8

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T(e contract acceptor


C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

8-.

The contract acceptor makes sure$ by )uality assurance measures or by certification from another licensed manufacturer$ that all raw materials received from any source meet relevant specifications and that all work in relation to those products or materials is carried out in compliance with re)uirements of this #ode of GMP The contract acceptor refrains from any activity that may adversely affect the )uality of the product manufactured and*or analysed for the contract giver 9here the contract acceptor is an analytical laboratory$ the contract acceptor makes available to the contract giver details of all analytical procedures carried out on the contract giver=s materials$ as well as details of any relevant validation studies carried out on those procedures !lternatively$ where the contract acceptor considers an analytical method to be confidential property$ that method and its validation are available to the !P;M! The contract acceptor makes available to the contract giver details of all manufacturing procedures and any )uality control tests carried out on the contract giver=s behalf$ as well as copies of relevant manufacturing records The contract acceptor does not pass to a third party any of the work entrusted to them under the contract without the prior evaluation and written consent of the contract giver !rrangements made between the contract acceptor and any third party are subject to a GMP !greement between either the original contract giver or the contract acceptor and the third party Those arrangements ensure that relevant manufacturing and analytical information is made available to the third party in the same way as between the original contract giver and contract acceptor The third party holds an !P;M! Manufacturers Cicence$ unless exempted under the !gricultural and ;eterinary #hemicals #ode @egulations -884 or otherwise authorised by the !P;M!$ as in the case of overseas manufacturers$ and accepts the same responsibilities as the contract acceptor Manufacturing$ analytical and distribution records$ and retention samples are kept as specified in the GMP !greement and in accordance with the !gricultural and ;eterinary #hemical #odes @egulations -884 (see also #hapter 4 G@ecords= of the GMP #ode) The contract acceptor has ade)uate premises and e)uipment$ knowledge and experience$ )uality management system and competent personnel to satisfactorily carry out the work ordered by the contract giver

8-8-1

8-2 8-3 8-4

8-6

8-7

"n&pection of contract manufacturer&


8-5 8-5 !udits of contract manufacturers by the contract giver or an agreed third party are carried out to ensure that work is carried out to re)uirements in accordance with GMP The depth and fre)uency of inspections are determined on a risk management basis

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,ey ob&er-ation& and comment& .Comment on bot( po&iti-e and ne%ati-e a&pect& of Contract Manufacture+ Record e-idence &i%(ted and re-ie/ed0 &uc( a& 3O*&+ $M* contract& and record&0 particularly /it( re&pect to non-conformance1 +

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CORE ELEMENT 1A Manufacturin% principle

"NTERNAL A!D"T3

Manufacturer& of -eterinary c(emical product& mu&t re%ularly and &y&tematically carry out internal audit& of all a&pect& of t(eir manufacturin% operation&0 a& /ell a& of t(eir 'uality a&&urance pro%ram0 in order to monitor compliance /it( t(eir aut(ori&ed procedure&0 &tandard& and re'uirement& and en&ure product 'uality+ 3tep& mu&t be ta)en to implement any nece&&ary correcti-e and pre-enti-e action identified by t(o&e internal audit& and to a&&e&& t(e outcome&+

$eneral
C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

-..-

! program of planned and documented internal audits (self&inspections) is in place to regularly and systematically assess all aspects of manufacture and )uality control for compliance with GMP and to assess the effectiveness of the )uality assurance system Those audits cover all aspects of manufacture The fre)uency 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 ?nternal 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 !lternatively$ independent external auditors are used 9here the need for corrective action has been identified$ steps are taken to address any observed deviations from the documented )uality system and manufacturing procedures #orrective and preventive actions are monitored for effectiveness and modified if necessary /ocumented procedures are amended if there is an identified need to do so @ecords 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

-..1

-..2

-..3

,ey ob&er-ation& and comment& .Comment on bot( po&iti-e and ne%ati-e a&pect& of Contract Manufacture+ Record e-idence &i%(ted and re-ie/ed0 &uc( a& 3O*& and record&0 particularly /it( re&pect to non-conformance1 +

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CORE ELEMENT 11 Manufacturin% principle&

COM*LA"NT3 AND *ROD!CT RECALL3

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 mar!etplace product that is !nown to be defective or is suspected of being defective.

Complaint&
C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

--.--.1 2 --.2 --.3 --.4 --.6

There are documented procedures for the handling of all complaints$ recalls and returned product There is in place a documented procedure for receiving$ recording$ reviewing and$ where appropriate$ acting upon all )uality&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 @ecords 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 !ll complaints related to product )uality are registered in a complaints register @ecords should also be kept of all product returned for other reasons$ the reason for the return (eg out of date product)$ and its disposal @ecords are also kept of any re)uired corrective action @esponsibility for handling complaints related to product )uality and for deciding the measures to be taken is delegated to a specified member or group of staff$ who are given ade)uate resources to carry out the task ?f this person is not the person responsible for )uality$ the latter are made aware of any such complaint or investigation involving products manufactured or handled on the premises The complaints procedure incorporates the !P;M!=s re)uirements for adverse experience reporting

--.7

3u&pected product defect&


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C(ec) *oint No+ C(ec)point Acceptable Minor non conformance

KP !"F##
Major non conformance Not Audited

--.5 --.8

?f a product defect is discovered or suspected in a batch$ other batches are checked in order to determine whether they also might be affected !ttention is paid to other batches that may contain reworks of the defective batch #omplaints records are reviewed regularly for any indication of specific or recurring problems re)uiring attention and possibly the recall of products

Recall&
--.The !P;M! is notified if a manufacturer is considering recall action following possibly faulty manufacture$ product deterioration$ or any other serious )uality problem with a product The competent authorities of all countries to which defective products may have been distributed are also notified There is a written procedure for the initiation and management of any recall activity$ which is aligned with the !P;M!=s guidelines for the recall of agricultural and veterinary chemical products and the re)uirements of the Trade Practices !ct Procedures are regularly checked and updated when necessary @esponsibility for execution and co&ordination of recalls is delegated to a specific member or group of staff$ who are given ade)uate 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 ?f this person is not the person responsible for )uality$ the latter is made aware of any recall operation @ecall 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 /istribution 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 @ecalled products are identified and stored separately in a secure area while awaiting a decision on their fate The progress of a recall is recorded and a final report issued$ including reconciliation between the delivered and recovered )uantities of products @ecords are kept of all recalls initiated (including internal Gdummy runs=)$ all action taken$ as well as of details of all product returned as a result of recalls and its disposal @ecords are in accordance with the !P;M!=s guidelines for the recall of agricultural and veterinary chemical products'

--..

---1

--.2

---3 ---4 ---6 ---7

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Recall& .cont1
C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

---5

The effectiveness of the recalls procedure is evaluated from time to time by means of internal Gdummy runs= and the procedure revised if necessary The outcome of these Gdummy runs= is recorded$ together with details of any corrective action considered necessary

,ey ob&er-ation& and comment& .Comment on bot( po&iti-e and ne%ati-e a&pect& of Complaint& and *roduct Recall&+ Record e-idence &i%(ted and re-ie/ed0 &uc( a& 3O*&0 record&0 etc0 particularly /it( re&pect to non-conformance1 +

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ANNEB 1 Manufacturin% principle&

3TER"LE *ROD!CT3

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.

*remi&e&
C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

!-&..!-&..1 !-&..2 !-&..3 !-&..4 !-&..6 !-&..7

:terile products are manufactured in areas that are designed and managed to minimise microbial and particulate contamination 9herever practicable$ enclosed systems are employed for product preparation and filling :inks and floor drains are excluded wherever possible 9here this is unavoidable$ air breaks are fitted between the machine and sink or drain #hanging 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 :eparate airlocks may be appropriate for moving some materials into controlled areas !n 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 Jnder 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

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*remi&e& .cont1
C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

!-&..5

! warning system is provided to indicate failure in the air supply ?ndicators of pressure differences are fitted between areas where these differences are important These pressure differences are recorded regularly or otherwise documented

*roduction area&
!-&..8 !ccess to buildings is restricted to authorised persons ;isitors are discouraged$ kept to a minimum$ and generally permitted only in areas not used for aseptic operations ;isitors= clothing is in accordance with the area visited !ll production areas are$ as far as possible$ designed to avoid the entry of non&operational personnel !ll 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 To reduce accumulation of dust and to facilitate cleaning$ there are no uncleanable recesses and a minimum of projecting ledges$ shelves$ cupboards and e)uipment /oors are designed to avoid uncleanable recesses Pipes$ ducts and other utilities are installed so that they do not create recesses$ unsealed openings and surfaces that are difficult to clean Balse ceilings are sealed to prevent contamination from the space above them !reas for the manufacture of terminally sterilised product are designed to prevent the mixing of sterilised and non& sterilised products

!-&.-.

!-&.-!-&.-1 !-&.-2 !-&.-3

3anitation and (y%iene


!-&.-4 !-&.-6 !-&.-7 !reas used for the production of sterile products are subjected to regular$ thorough cleaning and disinfection The effectiveness of controlling microbial content of the air and surfaces is routinely monitored ?tems brought into sterile manufacturing areas$ including means of transport$ are of a standard of cleanliness compatible with the environmental standard for the area There are specific written procedures for the% (a) cleaning of bulk containers and their subse)uent inspection for release for use in processing' (b) control of external contamination of bulk containers during use' (c) assembly of filters and the connecting of hoses and pipelines'

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3anitation and (y%iene .cont1


C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

(d) dismantling$ cleaning and decontamination of pumps$ filters$ pipelines$ and filling heads and for their subse)uent inspection for release for use in processing !-&.-5 Bumigation (with humidified formaldehyde vapour or other validated method) may be used to reduce microbial contamination in places inaccessible to surface disinfection Bogging (such as with peracetic acid) may also be acceptable if the process is validated /isinfectants and detergents are monitored for microbial contamination unless pre&sterilised /iluted disinfectants and detergents are kept in previously cleaned containers and are only stored for defined periods unless they are also sterilised

!-&.-8

En-ironmental control 6 air 'uality


A1-A2A @or t(e manufacture of &terile medicinal product&0 four %rade& of air 'uality are di&tin%ui&(ed0 a& follo/& $rade A9 The local Aone for high risk operations$ eg filling Aone$ stopper bowls$ open ampoules and vials$ aseptic connections Hormally such conditions are provided by a unidirectional airflow workstation Jnidirectional airflow systems should provide a homogeneous air velocity in the range of . 26(. 43 m*s (guidance value) at the working position in open cleanroom applications The maintenance of unidirectional airflow are demonstrated ! unidirectional airflow at lower velocities may be used in closed isolators and glove boxes This is the background environment for Grade ! Aone and is used for aseptic preparation and filling$ #lean areas for carrying out less critical stages in the manufacture of sterile products

$rade B9 $rade C:D9

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GMP Audit Checklist for MANUFACTURERS A1-A21 T(e cla&&ification of airborne particulate le-el& for $rade& A-D i& %i-en in t(e follo/in% table+ Ma4imum permitted number of particle&:m5 of %i-en &iCe.a1 $rade A B C D Note&9 (a) D A+8 m 24.. 24.. 24.... 24.....
c!

KP !"F##

At re&t

%!

"n operation D 8 m - d! - d! 1... 1.... D A+8 m 24.. 24.... 24..... :ee Hote e!
c!

%1

D 8 m - d! 1... 1.... :ee Hote e!

! discrete airborne particle counter is used to measure the concentration of particles of siAes e)ual to or greater than the designated threshold 9here consideration of particulate contamination is necessary to ensure product )uality$ a continuous measurement system are used for monitoring the concentration of particles in the Grade ! Aone$ and is recommended for the surrounding Grade F areas Bor routine testing$ the total sample volume are not less than -*mL for Grade ! and F areas and preferably also in Grade # areas ?n order to reach the F$ # and / air )uality grades$ the number of air changes are related to the siAe of the room and the e)uipment and personnel present in the room The air system are provided with appropriate terminal filters such as high efficiency particulate air (D"P!) filters for grades !$ F and #

(b)

The particulate conditions given in the table for the Gat rest= state are achieved after a short Gclean up= period of -4&1. minutes (guidance value) in an unmanned state after completion of operations The particulate conditions for grade ! Gin operation= given in the table are maintained in the Aone immediately surrounding the product whenever the product or open container is exposed to the environment ?t 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 The guidance given for the maximum permitted number of particles in the Gat rest= and Gin operation= conditions correspond approximately to the cleanliness classes in the !:*HM: ?:< -3633&- at a particle siAe of . 4 Nm These areas are expected to be completely free from particles of siAe greater than 4 Nm !s it is impossible to demonstrate the absence of particles with any statistical significance$ the limits are set to - particle*m 2 /uring the cleanroom )ualification it are shown that the areas can be maintained within the defined limits The re)uirements and limits will depend on the nature of the operations carried out

(c) (d)

(e) !-&.11

<ther 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

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GMP Audit Checklist for MANUFACTURERS !-&.12 E4ample& of operation& to be carried out in t(e -ariou& air 'uality %rade& $rade A C D $rade A C D Operation& for terminally &terili&ed product& Billing of products when unusually at risk Preparation of solutions when unusually at risk and filling of products Preparation of solutions and components for subse)uent filling Operation& for a&eptic preparation& !septic preparation and filling Preparation of solutions to be filtered Dandling of components after washing

KP !"F##

Air 'uality .cont1


C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

!-&.13

<perations preceding terminal sterilisation are normally carried out in at least a Grade / environment 9here there are increased risks of microbial contamination to the product (eg filling of wide&necked containers$ or where the product actively supports microbial growth or must be held before sterilisation)$ preparation of solutions and components is carried out in at least a Grade # environment ! floor plan of the manufacturing areas is available$ showing the points of entry and exit of air$ classification of each room$ number of air changes per hour and the differential pressure(s) 9here an isolator is used$ the air classification re)uired for the background environment depends on the design of the isolator and its application ?t is controlled and for aseptic processing is at least Grade / ?solators are introduced only after appropriate validation ;alidation takes into account all critical factors of isolator technology$ for example the )uality of the air inside and outside (background) the isolator$ sanitation of the isolator$ the transfer process and isolator integrity Monitoring of isolators is carried out routinely and includes fre)uent leak testing of the isolator and glove*sleeve system Flow*fill*seal e)uipment used for aseptic production that is fitted with an effective Grade ! air shower may be installed in at least a Grade # environment$ provided that Grade !*F clothing (see clause !-&.3-) is used The environment should comply with the viable and non&viable limits Gat rest= and the viable limit only when in operation Flow*fill*seal e)uipment used for the production of products for terminal sterilisation is installed in at least a Grade / environment

!-&.14 !-&.16 !-&.17

!-&.15 !-&.18

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En-ironmental monitorin%
C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

!-&.2.

#leanrooms and related areas are monitored at planned intervals for airborne and surface microbiological contamination and the results obtained used to determine Galert= and Gaction= levels Monitoring is fre)uent and takes place while normal production operations are in progress ?n the case of aseptic filling$ it provides the basis for the assessment of aseptic hygiene throughout the filling process @esults are tabulated or graphed and assessed and if necessary$ prompt remedial action taken according to the standards established !dditional 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 "nvironmental monitoring of clean areas includes the following components% (a) particulate monitoring during routine operation$ where relevant' (b) airborne microbiological monitoring' & & air samplers sample an ade)uate )uantity of air to provide a meaningful result (see note a$ clause !-& .1-)' air monitoring$ using both volumetric and settle plate&sampling methods in aseptic fill and seal areas'

!-&.2-

(c) microbiological monitoring of surfaces (eg walls$ e)uipment 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 -5O# and 24&4.P 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) !-&.21 !-&.22 !-&.23 The methods used for environmental monitoring are justified Microbiological and particulate contamination are controlled and monitored for each grade by a comprehensive procedure approved by )uality management staff 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 ?t is recommended that two types of culture media (usually agars) be used for the recovery of the above&mentioned organisms ?solates found during environmental monitoring are regularly identified

!-&.24

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*er&onnel
C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

!-&.26

Management delegate the supervision of the production process for sterile products only to persons who are )ualified by training and*or experience in the relevant aspects of pharmaceutical*microbiological sciences 9here the person responsible for 0uality is not a )ualified microbiologist$ arrangements are made to obtain regular external expert microbiological advice !ll 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 #hapter 1$ clauses 112&12.) and the basic elements of microbiology using expert microbiological advice 9hen 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 Personnel re)uired 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 haAard to the product The same principle is applied to visitors to clean rooms :taff 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 )uarantine exclusion from the manufacturing area 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 T(e minimum protecti-e clot(in% re'uirement& for eac( %rade of controlled area are a& follo/&9 $rade A:B9 Deadgear should totally enclose hair and$ where relevant$ beard and moustache' it are tucked into the neck of the suit ! facemask are worn to prevent the shedding of droplets :terilised$ 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 Dair and$ where relevant$ beard and moustache are covered Hon&powdered gloves are worn ! 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 Dair and$ where relevant$ beard and moustache are covered ! suitable protective garment and overshoes or dedicated shoes are worn Gloves (non& powdered) may be re)uired

!-&.27

!-&.25

!-&.28

!-&.3.

A1-A71

$rade C9 $rade D9

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E'uipment
C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

!-&.31 !-&.32 !-&.33

Jnidirectional airflow e)uipment is regularly tested and the results recorded 9here necessary$ e)uipment is sterilised before use The effect of the sterilisation methods on the operation and durability of e)uipment is considered !ll sterilisation procedures are validated ")uipment used in the processing of sterile products before sterilisation is designed and operated to minimise contamination by microorganisms and particulate matter !s far as practicable$ e)uipment$ fittings and services are designed and installed so that maintenance and repairs may be carried out without personnel having to enter the cleanroom ?f sterilisation is re)uired$ it is carried out after complete reassembly wherever possible Maintenance tools and e)uipment are cleaned$ disinfected or sterilised before use ;essels containing bulk sterile&filtered water or product are vented through bacteria&retaining filters !utoclaves$ gas sterilisers$ sterilising ovens$ and lyophilisers are e)uipped with automatic recorders that monitor the time and temperature and$ where necessary$ other parameters of the sterilising cycle This e)uipment is )ualified upon installation and is calibrated periodically @ecords confirm that these parameters have been achieved with an appropriate degree of accuracy ! 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 9here 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 Deat sterilisers have provision for the entry of leads from temperature sensing devices placed in product packs or simulated product packs during heat penetration studies The pressure during steam sterilising cycles is recorded at least manually :team used for sterilisation does not contain additives at a level that could cause contamination of product or e)uipment The use of Gclean steam= may need to be considered 9here the )uality 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 #ompressed air used is also filtered through a bacteria&retaining filter 9ater treatment plants and distribution systems are designed$ constructed and maintained so as to ensure a reliable source of water of an appropriate )uality They are not operated beyond their designed capacity 9ater is produced$ stored and distributed in a manner that prevents microbial growth' for example$ by constant circulation at a temperature above 5.O# or at 3O# or below

!-&.34 !-&.36

!-&.37

!-&.35 !-&.38 !-&.4. !-&.4-

!-&.41

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E'uipment .cont1
C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

!-&.42

!ll water systems supplying processed water for product manufacture are monitored for% (a) total organic carbon' (b) conductivity' (c) endotoxin' (d) microbial )uality

3pecification& for material&


!-&.43 !-&.44 !-&.46 :pecifications for raw materials consider microbial limits and any special storage re)uirements 9ater used in the preparation of sterile products complies with the relevant pharmacopoeial standards or registration re)uirements ?t may not need to be sterilised before the product is manufactured 9hen distilled water is used in the final product$ the time between distillation and the final production does not exceed 13 hours unless provision is made for it to be held at a temperature of at least 5.O# ! limit on the time that may elapse between solution preparation and sterilisation is also set

*roce&&in%
!-&.47 !-&.45 #ontainers or other materials liable to generate particles or fibres are not taken into areas supplied with Grade !$ F or # air The intervals between the washing$ drying and sterilisation of components$ containers and e)uipment 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 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 Jnless special storage conditions are provided$ bulk a)ueous 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 The microbiological load of products is as low as practicable before sterilisation ?t 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 !ll solutions and in particular$ large volume infusion fluids are passed through a filter of pore siAe Q . 34 Nm$ where possible immediately before filling

!-&.48

!-&.6.

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*roce&&in% .cont1
C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

!-&.6!-&.61 !-&.62 !-&.63

Fatch 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 e)uipment used 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 :terilisation records are reviewed and approved as part of the batch release procedure "ach separate sterilising basket$ package$ pallet$ etc$ of products or components undergoing sterilisation is fastened$ wired$ sealed$ lidded or otherwise secured to prevent mix&up ?t bears$ in a conspicuous position$ a visual indicator to demonstrate whether it has passed through a sterilisation cycle Microbiological indicators are )uarantined and subjected to )uality control before use 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 #omponents$ containers and e)uipment are handled after the final cleaning process in such a way that they are not re&contaminated "ach procedure used for the sterilisation of a particular )uantity 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 e)uipment 9here practicable$ heat sterilisation is the method of choice ?n any case$ the sterilisation process is in accordance with product registration ;alidated loading patterns are established for all sterilisation processes Fiological 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 )uality checked by positive controls ?f biological indicators are used$ strict precautions are taken to avoid transferring microbial contamination from them

!-&.64 !-&.66 !-&.67 !-&.65

!-&.68 !-&.7. !-&.7-

3terili&ation by (eat 6 %eneral i&&ue&


!-&.71 !-&.72 "ach heat sterilisation cycle is recorded on a time*temperature chart with a suitably large scale or by other appropriate e)uipment with suitable accuracy and precision #hemical or biological indicators may also be used$ but must not take the place of physical measurements

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3terili&ation by (eat 6 %eneral i&&ue& .cont1


C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

!-&.73

:ufficient time is allowed for the whole of the load to reach the re)uired temperature before measurement of the sterilising time is commenced This time is determined for each type of load Typical loading diagrams are part of the standard operating procedures "ach sterilising load contains one or more indicators to show that the cycle has been completed !fter the high&temperature phase of a heat sterilisation cycle$ precautions are taken to prevent contamination of a sterilised load during cooling !ny cooling fluid or gas in contact with the product is sterilised$ unless it can be shown that any leaking container would not be approved for use

!-&.74

3terili&ation by moi&t (eat


!-&.76 Foth temperature and pressure are used to monitor the process #ontrol instrumentation is independent of monitoring instrumentation and recording charts 9here automated control and monitoring systems are used for these applications$ they are validated to ensure that critical process re)uirements are met :ystem and cycle faults are registered by the system and evident to the operator The reading of the independent temperature indicator is routinely checked against the chart recorder during the sterilisation period The items to be sterilised are wrapped in a material that allows removal of air and penetration of steam but prevents recontamination after sterilisation !ll parts of the load are in contact with the sterilising agent at the re)uired temperature for the re)uired time

!-&.77

3terili&ation by dry (eat


!-&.75 ")uipment for dry heat sterilisation allows air circulation within the chamber and the maintenance of a positive pressure to prevent the entry of non&sterile air !ny air admitted is passed through a D"P! filter 9here this process is also intended to remove pyrogens$ challenge tests using endotoxins are used as part of the validation

3terili&ation by radiation
!-&.78 The radiation dose is measured during the sterilisation procedure Bor this purpose$ dosimetry indicators that are independent of dose rate are used$ giving a )uantitative 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 9here plastic dosimeters are used$ they are used within the time limit of their calibration /osimeter absorbances are read soon after exposure to radiation Fiological indicators may be used as an additional control
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3terili&ation by radiation .cont1


C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

!-&.5!-&.51

;alidation procedures ensure that the effects of variations in density of the packages are considered Materials handling procedures prevent mix&up between irradiated and non&irradiated materials @adiation& sensitive colour indicators are also used on each package to differentiate between packages that have been subjected to irradiation and those that have not The total radiation dose is administered within a pre&determined time span ?f an outside contractor carries out sterilisation by radiation$ the contract giver is responsible for ensuring that the re)uirements for this type of sterilisation are met and that the process is validated The responsibilities of the radiation plant operator (eg for using the correct dose) are also be specified Jltraviolet irradiation is not normally an acceptable method of sterilisation

!-&.52 !-&.53

!-&.54

3terili&ation by et(ylene dio4ide


!-&.56 This method is only used when no other method is practicable /uring process validation$ it is shown that there is no damaging effect on the product and that the conditions and time allowed for degassing are such as to reduce any residual gas and reaction products to defined acceptable limits for the type of product or material Fefore exposure to the gas$ materials are brought into e)uilibrium with the humidity and temperature re)uired for the process The time re)uired for this is balanced against the opposing need to minimise the time before sterilisation "ach sterilisation cycle is monitored with suitable biological indicators$ using the appropriate number of test pieces distributed throughout the load The information so obtained forms part of the batch record Bor each sterilisation cycle$ records are made of the time taken to complete the cycle$ the pressure$ temperature and humidity within the chamber during the process and the gas concentration and the total amount of gas used The pressure and temperature are recorded throughout the cycle on a chart These records should form part of the batch record

!-&.57

!-&.55 !-&.58

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3terili&ation by filtration
C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

!-&.8.

:olutions or li)uids are filtered through a sterile filter of nominal pore siAe of Q. 11 Nm$ or with at least e)uivalent micro&organism retaining properties$ into a previously sterilised container #onsideration is given to complementing the filtration process with heat or other treatment where the presence of filterable microorganisms is suspected 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 Bibre&shedding characteristics of filters are minimal !sbestos&containing filters are not used under any circumstances The same filter is not used for more than one working day$ unless such use has been validated The filter does not affect the product by removal of ingredients from it or by release of substances into it 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 ?ntegrity 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 @esults 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

!-&.8!-&.81 !-&.82 !-&.83 !-&.84

@ini&(in% .*rimary pac)a%in%1


!-&.86 #ontainers are closed by appropriately validated methods #ontainers closed by fusion (eg glass or plastic ampoules) are subject to -..P integrity testing :amples of other containers are checked for integrity according to appropriate procedures #ontainers sealed under vacuum are tested for maintenance of that vacuum after an appropriate$ pre&determined period Billed containers of parenteral products are inspected individually for extraneous contamination or other defects 9hen inspection is visual$ it is done under suitable and controlled conditions of illumination and background <perators doing the inspection are subjected to and pass regular eyesight checks$ with spectacles if worn$ and are allowed fre)uent breaks from inspection 9here other methods of inspection are used$ the process is validated and the performance of the e)uipment checked at intervals @esults are recorded

!-&.87 !-&.85

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uality control
C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

!-&.88

9here re)uired or appropriate$ tests for the following are carried out on each batch of product Bor 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

!-&-.. !-&-.!-&-.1 !-&-.2

#umulative records of environmental control$ the testing of manufacturing e)uipment$ media fill runs and all other applicable )uality control tests are maintained by 0uality #ontrol Pharmacopoeial methods are used for sterility tests These methods are validated for the product(s) concerned 9here parametric release has been authorised$ all calibrations and controls that were specified in the application for authorisation are rigorously maintained :amples 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

!-&-.3

@elease 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) e)uipment monitoring and performance records' (e) finished product test records

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A&eptic proce&&in%
*remi&e&
C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

!-&-.4 !-&-.6 !-&-.7

!septic filling involves the minimum of human intervention :inks and drains are excluded from aseptic filling*sealing rooms !irlocks are flushed effectively with filtered air The final stage of the changing room is$ in the Gat rest= state$ the same grade as the area into which it leads :eparate changing rooms for entering and leaving clean areas are provided where desirable Dand&washing facilities are provided only in the first (outer) stage of the changing rooms !djacent rooms of different grades have a pressure differential of -.&-4 pascals (guidance values) The air&flow pattern$ location of e)uipment and movement of personnel affords protection of the Aone of greatest risk (ie the immediate environment to which a product and sterilised components that contact the product are exposed)

!-&-.5

*roduction area&
!-&-.8 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 ?t is desirable to maintain this room at a positive pressure relative to the outside environment Hon&sterile products are not processed in the same area as sterile products Grade F areas (see clause !-&.1.) are designed so that all operations can be observed from the outside

!-&--. !-&---

3anitation and (y%iene


!-&--1 !-&--2 /uring aseptic operations$ the areas are not used for any other purpose !fter any non&sterile operation such as maintenance$ and before aseptic operations are commenced$ the areas are thoroughly cleaned and disinfected #lean and$ where necessary$ sterile protective clothing is supplied and worn in production areas Personnel working in associated areas not designated as clean or aseptic areas change into clean over&garments before entering the clean or aseptic areas and remove these over&garments on exit These outer garments are not worn outside the clean&room suite #lean over&garments are made of such material and weave that they are comfortable to wear$ do not shed fibres$

!-&--3

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KP !"F##

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3anitation and (y%iene .cont1


C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

!-&--4

/isinfectants and detergents used in Grade ! and F areas are sterile before use

En-ironmental control
!-&--6 A1-11= $rade A The Gin operation= and Gat rest= states are defined for each clean room or suite of clean rooms E4ample& of operation& to be carried out in t(e -ariou& clean Cone %rade& Operation& for a&eptic preparation& Preparation of solutions that are not to be filtered Dandling of sterile starting materials and components that are not to be filtered Dandling and filling of aseptically prepared products Transfer of partially closed containers$ as used in freeAe drying Preparation and filling of sterile ointments$ creams$ suspensions and emulsions Transfer of partially closed containers in sealed transfer trays Preparation of solutions to be filtered Dandling of components after washing

B C D

En-ironmental monitorin%
!-&--5 :ampling methods used during operation do not interfere with Aone protection @esults from monitoring are considered when reviewing batch documentation for finished product release :urfaces and personnel are monitored after critical operations !dditional microbiological monitoring may be appropriate after activities such as major maintenance$ interruption to production and e)uipment validation

!-&--8

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GMP Audit Checklist for MANUFACTURERS A1-12A $rade Recommended limit& to be u&ed in microbiolo%ical monitorin% of clean area& %a& durin% operation9 Air &ample cfu:m5 R-. -.. 1.. (a) (b) 3amplin% met(od 3ettle plate& .diam+ Contact plate& ?Amm1 cfu:7 (our& .diam+ 88mm1 %b& cfu:plate RR4 4 4. 14 -.. 4. $lo-e print .8 fin%er&1 cfu:%lo-e R4 & &

KP !"F##

A B C D Note&9

These are average values ?ndividual settle plates may be exposed for less than 3 hours$ but should not be exposed for more than 3 hours unless validated !dditional plates may be used at a single location to sum to four hours exposure The results from settle plates should not be interpreted as e)uivalent to those from volumetric sampling cfu S colony forming units

En-ironmental monitorin% .cont1


C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

!-&-1-

?t can be demonstrated that airborne cleanliness classifications are met during operations !ppropriate alert and action limits are set for the results of particulate monitoring <perating procedures prescribe corrective action$ if these limits are exceeded

*er&onnel
!-&-11 <nly the minimum number of personnel essential for production and in&process control operations are allowed in aseptic or clean areas$ particularly during aseptic processing ?nspections and controls are conducted outside the clean areas as far as possible Personnel engaged in servicing e)uipment or other non&routine activities observe the same precautions and hygiene standards as production personnel 9rist watches$ make&up and jewellery are not worn in clean areas <utdoor clothing is not brought into changing rooms leading to Grade F and # rooms #lean sterile (sterilised or ade)uately sanitised) protective garments are provided at each work session for every worker in a Grade !*F area Gloves are regularly disinfected during operations Masks and gloves are changed at least at every working session

!-&-12 !-&-13 !-&-14

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*er&onnel .cont1
C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

!-&-16

#lean 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 :eparate laundry facilities are provided for such clothing

E'uipment
!-&-17 ! conveyor belt should not pass through a partition between a Grade ! or F area and a processing area of lower air cleanliness$ unless the belt itself is continually sterilised (eg in a sterilising tunnel)

*roce&&in%
!-&-15 !ctivities 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 #omponents$ containers$ e)uipment and any other article re)uired 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 Hon&combustible gases are passed through microorganism&retentive filters ;alidation 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 (D;!#) system$ e)uipment$ process or number of shifts The number of containers used for media fills is sufficient to enable a valid evaluation Bor small batches$ the number of containers for media fills is at least e)ual to the siAe of the product batch The target is Aero growth$ but production need not be halted if a contamination rate of less than . -P is observed The manufacturer has establish alert and action limits #are is taken that any validation does not compromise the processes

!-&-18

!-&-2.

!-&-2-

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,ey ob&er-ation& and comment& .Comment on bot( po&iti-e and ne%ati-e a&pect& of 3terile *roduct manufacture+ Record e-idence &i%(ted and re-ie/ed0 &uc( a& 3O*&0 record&0 ob&er-ation&0 etc0 particularly /it( re&pect to non-conformance1 +

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ANNEB 2 Manufacturin% principle&

"mmunobiolo%ical& and ot(er product& of biolo%ical ori%in

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 contamination6 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 to$ic 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 !eeping meticulous records of their origin and disposition

*remi&e&-%eneral
C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

!1&..-

/ocumentation 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 !nimal species accommodated in animal houses or otherwise on the site are identified on the site plans or accompanying notes !ctivities 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

!1&..1 !1&..2

*remi&e& - 3e%re%ation and containment


!1&..3 Premises are designed in such a way as to control both the risk to the product and to the environment This can be achieved by the use of clean contained and*or controlled areas

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*remi&e& - 3e%re%ation and containment .cont1


C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

!1&..4 !1&..6 !1&..7 !1&..5

Cive biological agents are handled in contained areas that may also be clean areas The level of containment should depend on the pathogenicity of the microorganism and whether it has been classified as exotic ?nactivated biological agents are handled in clean areas #lean areas are also used when handling non&infected cells isolated from multi&cellular organisms and filtration&sterilised media <pen circuit operations involving non&viable products or components not subse)uently sterilised are carried out within a unidirectional Grade ! airflow workstation in a Grade F area <ther operations where live biological agents are handled$ such as )uality control$ research and diagnostic services$ are contained and separated if production operations are carried out in the same building The movement of personnel and the level of containment should depend on the pathogenicity and origin of the biological agents 9here there is the risk of introducing highly pathogenic or exotic organisms (eg via )uality control activities)$ the level of containment is ade)uate to cope with all such risks #ontainment may also be re)uired if )uality control or other activities are carried out in buildings in close proximity to those used for production #ontained areas have the characteristics detailed below (a) They are capable of easy disinfection (b) They have no direct venting to the outside (c) ;entilation systems have pressure differentials to contain organisms from the environment and protect the product from external contamination !ir is extracted through filters appropriate to the organisms being handled and not recirculated except to the same area Dowever$ the recycling of air between areas may be permissible$ provided it is appropriately filtered (d) They have a system for the collection and disinfection of li)uid effluents$ including contaminated condensate from sterilisers$ bioreactors etc :olid wastes$ including animal carcasses$ are disinfected$ sterilised or incinerated as appropriate #ontaminated filters are removed using a safe method (e) They have changing rooms designed and used as air locks$ and e)uipped with washing and showering facilities as appropriate !ir pressure differentials are such that there is no flow of air between the work area and the external environment or risk of contamination of outer clothing worn outside the area (f) !n air lock system for the passage of e)uipment$ is constructed so that there is no flow of contaminated air between the work area and the external environment$ or risk of contamination of e)uipment within the lock The air lock is of a siAe that enables the effective surface decontamination of materials being passed through it ?t is preferable that a timing device is installed on the door interlock to allow sufficient time for the decontamination process to be effective

!1&..8

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*remi&e& - 3e%re%ation and containment .cont1


C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

(g) There is a barrier double&door autoclave for the secure removal of waste materials and introduction of sterile items$ where appropriate (h) Transfer hatches and changing rooms have an interlock mechanism or other appropriate system to prevent the opening of more than one door at a time #hanging rooms are supplied with air filtered to the same standard as that for the work area$ and are exhausted to produce an ade)uate air circulation independent of that of the work area Transfer hatches are normally ventilated in the same way$ but unventilated hatches$ or those e)uipped with supply air only$ may be acceptable !1&.-9ith the exception of blending and subse)uent filling operations$ only one biological agent at a time is handled within an area Production operations such as cell maintenance$ media preparation$ or virus culture likely to cause contamination are not performed in the same area at the same time 9here the same room is used for more than one purpose$ effective decontamination and line clearance between operations are in place Production areas where biological agents particularly resistant to disinfection (eg spore&forming bacteria) are handled are separated and dedicated to that particular purpose until the biological agents have been inactivated >illed vaccines are blended$ filled$ and sealed under aseptic conditions and segregated from the processing areas where culturing is carried out The filling of containers with live vaccines$ including those prepared from attenuated strains$ is appropriately separated from other aseptic filling operations This may be achieved by using separate areas or by elapsed time and effective decontamination procedures

!1&.-1 !1&.-2 !1&.-3

*remi&e& -3anitation0 di&infection and /a&te di&po&al


!1&.-4 :anitation$ disinfection$ decontamination and disposal of wastes and effluents are particularly important in the manufacture of immunobiological and other biological products Procedures and e)uipment protect the product and avoid environmental contamination !utoclaving and incineration are the preferred methods of decontamination of rubbish and waste material$ although chemical inactivation may be acceptable in some circumstances Production areas are thoroughly cleaned and disinfected after any non&sterile operation$ such as maintenance and before aseptic processing resumes

!1&.-6

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*er&onnel
C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

!1&.-7

?n the case of biological agents known to cause disease in humans$ ade)uate measures are taken to prevent infection of personnel working with live organisms or with animals 9here relevant$ personnel are appropriately vaccinated and subject to regular medical examination !de)uate measures are taken to prevent biological agents being carried outside the manufacturing plant by personnel /ependent on the type of biological agent$ such measures may include complete changing of clothes and compulsory showering before leaving the production area 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 <nly personnel essential for production and in&process control operations$ maintenance and cleaning are allowed into processing areas Personnel working in areas designated as Gclean*aseptic= or Gculturing= 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

!1&.-5

!1&.-8

!1&.1. !1&.1-

E'uipment
!1&.11 !ny closed e)uipment used for the primary containment of biological agents is designed and constructed to prevent any leakage or the formation of droplets and aerosols ?nlets and outlets for gases are protected to achieve ade)uate 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 :eparate incubators are used for infected and non&infected containers and also generally for different organisms or cells ?ncubators containing more that one organism or cell type will only be acceptable if ade)uate measures are in place to seal$ surface decontaminate and segregate the containers !ll containers are individually labelled ")uipment used for the storage of biological agents or products is designed and used in such a manner as to prevent any possible mix&up !ll stored items are clearly and unambiguously labelled and kept in leak&proof containers ?tems such as seed stock (cell or organism) are stored in dedicated e)uipment Bor single&ended freeAe&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 /ouble&door freeAe& driers are sterilised after each cycle unless opened in a clean area :terilisation of freeAe&driers is done at least after each campaign

!1&.12

!1&.13

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E'uipment .cont1
C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

!1&.14 !1&.16

")uipment 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 ?n heat sterilising processes$ steps are taken to ensure that the whole load reaches the sterilisation temperature !ccount is taken of heat&up times for various loads and Gtypical loading= diagrams are part of standard operating procedures :tandard operating procedures are available ?tems 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 :terilisation 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 9hen re&useable filters are used$ they are effectively cleaned and sterilised after each use #onsideration is given to using individual filters for one type of solution only Jnidirectional airflow e)uipment is regularly tested and the results recorded #leanrooms and related areas are monitored at planned intervals for microbiological contamination

!1&.17 !1&.15

!1&.18 !1&.2.

Animal& and animal (ou&e&


!1&.2The sanitary status of the animals used for production is defined$ monitored$ and recorded !nimals are handled in ways defined in specific monographs (e g specific pathogen free T:PBU flocks)$ where these are available and relevant !nimals$ biological agents and tests carried out are identified in such a way as to prevent any risk of confusion and to control all foreseeable haAards !nimal testing facilities are sufficiently secure to ensure that unauthorised entry is prevented and that animals cannot break in or escape This applies particularly to facilities where live challenge tests are being carried out Procedures are in place to ensure that animals cannot be incorrectly identified or otherwise mixed up by staff !ttention is also given to decontamination and environmental re)uirements$ where applicable !nimal houses accommodating animals used for$ or intended to be used for$ production purposes are provided with appropriate containment and*or clean area measures and are separated from other animal accommodation !nimal houses accommodating animals that are used for )uality control purposes that involve pathogenic biological agents are ade)uately contained

!1&.21 !1&.22

!1&.23 !1&.24

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*roduction - %eneral
C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

!1&.26

Production of biological agents may take place in either clean or controlled areas$ provided it is carried out in totally enclosed and heat sterilised e)uipment$ with all connections being also heat sterilised after making and before breaking ?t may be acceptable for connections to be made under local unidirectional airflow$ provided these are few in number and proper aseptic techni)ues are used and there is no risk of leakage The sterilisation parameters used before breaking the connections are validated for the organisms being used /ifferent products may be placed in different bioreactors within the same area$ provided that there is no risk of accidental cross& contamination Dowever$ organisms generally subject to special re)uirements for containment are in areas dedicated to such products #ritical procedures$ including methods for sterilisation$ disinfection$ virus removal and inactivation$ are validated and subject to monitoring and in&process controls :ubstances of animal origin are prepared from homogeneous bulk material$ designated with a batch number ! 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

!1&.27 !1&.25

*roduction - &tartin% material&


!1&.28 9ritten specifications for starting materials$ where appropriate$ include details of the supplier$ the method of manufacture$ the geographical origin and the animal species from which the materials are derived The controls to be applied to starting materials are included Microbiological controls are particularly important The results of tests on starting materials comply with the specifications 9here the tests take a long time$ it may be necessary to process starting materials before the results of analytical controls are available ?n such cases$ the release of a finished product is conditional upon satisfactory results of the tests on starting materials 9here substances of animal origin (eg trypsin and serum albumin) are used as ingredients of culture media$ during processing or as added constituents of vaccines or diluents$ batch records allow traceability and confirmation with registered specifications and )uarantine re)uirements for all such substances

!1&.3.

!1&.3-

*roduction - media
!1&.31 !1&.32 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 9here heat&labile media components are re)uired$ these are sterilised by other acceptable means (eg filtration$ gamma irradiation) and added aseptically to the heat&sterilised base medium

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*roduction - &eed lot and cell ban) &y&tem


C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

!1&.33 !1&.34

?n order to prevent unwanted genetic drift$ the production of immunobiological products obtained by microbial$ cell or tissue culture$ or propagation in embryos and animals$ are based on a system of seed lots and*or cell banks The origin$ history since receipt$ preparation$ form and storage conditions of seed material are described in full The number of generations (doublings$ passages) between the master seed lot or cell bank and the finished product is defined and consistent with the product registration :eed lots and cell banks are ade)uately characterised and tested for contaminants !cceptance criteria for new seed lots and cell banks are established /uring the establishment of a seed lot or cell bank$ no other living or infectious material is handled at the same time in the same area or by the same person :eed lots and cell banks are established$ stored and used in such a way as to minimise the risks of mis&identification$ contamination or any alteration "vidence of the stability and recovery of the seeds and cell banks is generated and recorded :torage containers are secure$ clearly labelled and held at an appropriate temperature :torage conditions are properly monitored !n inventory of each seed lot and cell bank is maintained and each container accounted for <nly authorised personnel are allowed to issue and handle seed material

!1&.36

!1&.37

!1&.35

*roduction 6 operatin% tec(ni'ue&


!1&.38 The formation of droplets and the production of foam is avoided or minimised during manufacturing processes #entrifugation and blending procedures that may lead to droplet formation are carried out in appropriate clean or contained areas to prevent transfer of live organisms There are documented procedures for the prompt handling of spillages of live organisms ;alidated decontamination measures are available for each organism 9here different strains of a single species of bacteria or very similar viruses are involved$ the process need be validated against only one of them$ unless there is reason to believe that they may vary significantly in their resistance to the agent(s) involved <perations involving the transfer of materials such as sterile media$ cultures or product are carried out in pre& sterilised closed systems wherever possible 9here this is not possible$ transfer operations are protected by unidirectional airflow workstations #hecks are made to ensure that vessels are correctly connected when addition of cultures takes place !fter connection$ before the flow of product$ and again before disconnection fermenter sampling$ addition ports and connectors are sterilised with steam Dowever$ in some circumstances$ chemical disinfection of ports and unidirectional air flow protection of connections may be acceptable

!1&.4.

!1&.4-

!1.41

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*roduction 6 operatin% tec(ni'ue& .cont1


C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

!1&.42

")uipment$ glassware$ the external surfaces of product containers and other such materials are disinfected using a validated method before transfer from a clean or contained area <nly the absolute minimum of batch documentation enters and leaves the area ?f obviously contaminated$ such as by spills or aerosols$ or if the organism involved is an exotic$ the paperwork must be ade)uately disinfected through an e)uipment transfer hatch$ or the information transferred out by alternate means Ci)uid or solid wastes are sterilised or disinfected before transfer from a clean or contained area Dowever$ alternative transfer procedures may be appropriate in some cases !rticles and materials$ including documentation$ entering a production room are carefully controlled to ensure that only materials concerned with production are introduced !ll materials entering a clean or contained area are sterilised 9here practicable$ heat&stable articles and materials entering a clean or contained area do so through a double&ended autoclave or oven :terilisation of articles and materials elsewhere is acceptable$ provided they enter through an airlock and appropriate precautions are taken (eg double wrapping$ surface disinfection) Precautions are taken to avoid contamination or confusion during incubation There is a cleaning and disinfection procedure for incubators 9ith the exception of blending and subse)uent filling operations$ or when totally enclosed systems are used$ only one live biological agent is handled within a production room at any given time Production rooms are effectively disinfected between the handling of different live biological agents !ddition of inactivating agent to the bulk material is immediately followed by stirring or mixing to ensure even distribution of the agent The bulk material is then transferred to a sterile inactivation vessel to ensure all of the bulk material is exposed to the inactivating agent ;essels containing inactivated product are not opened or sampled in areas containing live biological agents !ll subse)uent processing of inactivated products takes place in Grade !*F clean areas or enclosed e)uipment dedicated to inactivated products #ontainers of bulk material are sealed$ appropriately labelled and stored under specified conditions There is a system to assure the integrity of all containers and their closures after filling This re)uirement applies to containers of bulk materials$ intermediates and finished products The capping of vials containing live biological agents is performed in such away that contamination of other products$ or escape of the live agents into other areas or the external environment$ does not occur

!1&.43 !1&.44 !1&.46

!1&.47 !1&.45

!1&.48

!1&.6.

!1&.6!1&.61 !1&.62

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*roduction 6 operatin% tec(ni'ue& .cont1


C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

!1&.63

9hen there is a delay between the filling of final containers and their labelling and packaging$ procedures are specified for the storage of unlabelled containers so as to preserve product identity and to ensure satisfactory storage conditions

uality control
!1&.64 !1&.66 !1&.67 !1&.65 !1&.68 ?n&process controls that are crucial to product )uality$ but which cannot be carried out on the finished product$ are performed at an appropriate stage of production 9here testing of bulk or intermediate materials is re)uired$ a sufficient )uantity of sample is retained$ under appropriate storage conditions$ to allow repetition or confirmation of the test result if necessary 9here production of a biological product involves continuous culture$ the )uality control re)uirements arising from such a production method are appropriately addressed :ufficient )uality control testing is undertaken to ensure that the product complies with the approved registration particulars 0uality #ontrol maintains cumulative records of environmental control$ the testing of manufacturing e)uipment and all other )uality control tests where applicable$ and takes into account the results of such testing before releasing any batch of product for distribution

,ey ob&er-ation& and comment& .Comment on bot( po&iti-e and ne%ati-e a&pect& of t(e manufacture of "mmunobiolo%ical and ot(er Biolo%ical product&+ Record e-idence &i%(ted and re-ie/ed0 &uc( a& 3O*&0 record&0 ob&er-ation&0 etc0 particularly /it( re&pect to non-conformance1 +

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NON-3TER"LE TEERA*E!T"C *ROD!CT3 .ot(er t(an ectopara&iticide&0 premi4e&0 &upplement& and biolo%ical feed additi-e&1
ANNEB 5
C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

!2&..!2&..1 !2&..2 !2&..3

Production areas where the product or cleaned production e)uipment are exposed are ade)uately protected from the outside environment The chemical and microbiological )uality of water used for production are specified and monitored Mixing and filling processes ensure homogeneity Procedures are in place to ensure that homogeneity is maintained during filling and after stoppages 9hen the finished product is not packaged immediately after processing$ the maximum period of storage and the storage conditions are specified and respected :pecial measures are taken to minimise microbial contamination of li)uids$ creams$ pastes$ gels and ointments' and to ensure that water )uality is appropriate :pecial measures are taken to minimise cross&contamination and facilitate cleaning in powder and tablet making facilities 9here penicillins and other highly sensitising materials are used$ special measures are taken to avoid cross& contamination and protect operators 9here products such as bloat oils and slow release intra&ruminal devices are made in +non&pharmaceutical, facilities$ steps are taken to ensure that relevant aspects of GMP are complied with

,ey ob&er-ation& and comment& .Comment on bot( po&iti-e and ne%ati-e a&pect& of Non-3terile T(erapeutic product manufacture+ Record e-idence &i%(ted and re-ie/ed0 &uc( a& 3O*&0 record&0 ob&er-ation&0 etc0 particularly /it( re&pect to non-conformance1 +

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ANNEB 7
C(ec) *oint No+ C(ec)point

EERBAL *ROD!CT3
Acceptable Minor non conformance Major non conformance Not Audited

!3&..!3&..1

:ome plants$ extracts$ tinctures and other preparations may re)uire special conditions of humidity$ temperature or light protection These conditions are provided and monitored !part from the re)uirements described in the core elements of this code (see #hapter 4)$ specifications for medicinal crude plants include$ as far as possible% 1 2 3 4 6 7 5 the full botanical name (including$ if appropriate$ the name of the originator of the classification$ eg Cinnaeus)' the preferred source of the plant (country or region of origin and$ where applicable$ method of cultivation$ time of harvesting$ collection procedure$ pesticides that can*cannot be used$ etc)' plant description$ including macroscopic and microscopic details$ where a whole plant is sourced' an authentic reference specimen is available for identification purposes' the part of the plant re)uired (ie whether the whole plant or only a specific part such as the roots$ leaves$ whole top$ etc)' the method used for drying' a physical description of the material' suitable identification tests$ including$ where appropriate$ tests for known active ingredients$ or markers$ and the limits accepted ' acceptable levels of possible chemical or biological contamination (pesticide$ fungicide$ herbicide$ fungal and*or microbial$ including aflatoxins$ pest infestations$ toxic metals$ and other possible contaminants and adulterants)$ as well as the methods used to determine such contamination' tests for foreign materials

!3&..2

!ny treatment used to reduce fungal*microbial contamination or other infestation is documented :pecifications for such procedures are available and include details of processes$ tests and limits for residues

,ey ob&er-ation& and comment& .Comment on bot( po&iti-e and ne%ati-e a&pect& of Eerbal product manufacture+ Record e-idence &i%(ted and re-ie/ed0 &uc( a& 3O*&0 record&0 ob&er-ation&0 etc0 particularly /it( re&pect to non-conformance1 +

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ANNEB 8
C(ec) *oint No+ C(ec)point

ECTO*ARA3"T"C"DE3
Acceptable Minor non conformance Major non conformance Not Audited

!4&..-

"ctoparasiticides are made in segregated areas or separate buildings$ using e)uipment that is dedicated to this type of product Jse of common e)uipment may be accepted$ provided that cross&contamination is controlled by scheduling and use of a validated cleaning procedure 9here ectoparasiticides are manufactured in a facility that also manufactures agricultural chemicals$ they are made in a separate area of the plant$ using e)uipment dedicated to veterinary chemical manufacture :pecial measures are taken to prevent cross&contamination with agricultural chemicals$ particularly where shared facilities$ such as packing rooms$ are used Funding is used where necessary to meet the re)uirements of dangerous goods and environment protection legislation 9here high volume materials (eg solvents in 1.. litre drums) are stored out&doors$ they are in ade)uately sealed containers and outside storage conditions are unlikely to adversely affect their )uality Manufacturing processes that involve the application of a li)uid premix onto an inert carrier powder ensure ade)uate dispersion of the li)uid and$ therefore$ the active ingredient(s) Mixing times and methods ensure batch homogeneity Measures are in place to prevent cross&contamination from hoses$ fixed pipe&work and connections

!4&..1

!4&..2 !4&..3 !4&..6

!4&..7

,ey ob&er-ation& and comment& .Comment on bot( po&iti-e and ne%ati-e a&pect& of Ectopara&iticide manufacture+ Record e-idence &i%(ted and re-ie/ed0 &uc( a& 3O*&0 record&0 ob&er-ation&0 etc0 particularly /it( re&pect to non-conformance1 +

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ANNEB <
C(ec) *oint No+

*REM"BE30 3!**LEMENT3 AND B"OLO$"CAL @EED ADD"T";E3


C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

!6&..-

The manufacture of dry premixes and supplements is carried out in dedicated areas that are separated from other aspects of veterinary chemical manufacture either by distance or by physical barriers$ in order to minimise the risk of cross&contamination #leaning programs specifically address the buildup of dust$ sticky materials such as molasses$ and corrosive materials such as salt !n effective pest control program is in place "xternal driveways and paths surrounding the manufacturing area are sealed to prevent the tracking of dirt and other external contaminants on the wheels of forklifts and other mobile e)uipment into the production areas 9here premixes and supplements are manufactured in premises also used to manufacture other products$ the staff involved in the manufacture of premixes and supplements are clearly identified and trained in those elements of GMP appropriate to their need #omplete cleaning of e)uipment may not be re)uired between batches of the same or closely related products$ provided that product integrity is maintained Parts of the process likely to have a significant adverse influence on the stability of the active ingredients (eg use of steam in pellet manufacture)$ are controlled to ensure batch&to&batch consistency :pecial attention is paid to the prevention of microbial contamination during manufacture or storage of susceptible li)uid formulations

!6&..1 !6&..2 !6&..3 !6&..4

!6&..6 !6&..7 !6&..5

Mined mineral &upplement&


The identity of mined material is checked by appropriate means :tockpiled material is protected from contamination by storm&water run&off and other environmental contaminants :teps are taken to ensure that bagged material is free from contamination such as pieces of metal$ broken glass$ bird droppings$ etc

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Direct-fed microbial& and enCyme product&


C(ec) *oint No+ C(ec)point Acceptable Minor non conformance Major non conformance Not Audited

!6&..8 !6&.-.

The air supply to the areas used for the production of direct&fed microbials and enAyme products is designed to minimise contamination Personnel responsible for the manufacture and )uality of direct&fed microbials and enAyme products have appropriate )ualifications in microbiology or related subjects and*or experience in the manufacture of such products 9here manufacture of direct&fed microbials and enAyme products is carried out in premises also used to manufacture other products$ the staff involved in the manufacture of direct&fed microbials and enAyme products are clearly identified and trained in those elements of GMP appropriate to their need The taxonomic identity of microorganisms selected for direct&fed microbials or enAyme production is checked Master seed cultures are checked for identity by morphological characterisation and comparison with the taxonomic characteristics originally identified Their purity is checked before transfer to the fermentation e)uipment by serial dilution$ plating and macroscopic and microscopic inspection for any foreign microorganisms Master seed cultures are maintained in such a way as to minimise degeneration and maintain genetic stability !ll seed cultures are clearly labelled and strict aseptic techni)ues applied in revival and subculture !ll operations are designed to avoid contamination$ formation of undesirable by&products$ deterioration and handling errors #ulture li)uids are sampled and checked for purity at regular intervals throughout the fermentation process Dowever$ in semi&solid surface cultivation$ purity control may be restricted to visual inspection "nAyme activity and operational parameters such as temperature$ pD and oxygen content$ are monitored during fermentation and kept within predetermined ranges based on experience /eviations from these ranges may indicate a contamination before it can be detected in microbial assays :teps are taken to ensure that contamination of the product during recovery is minimised

!6&.--

!6&.-1 !6&.-2

!6&.-3 !6&.-4 !6&.-6 !6&.-7 !6&.-5

!6&.-8

,ey ob&er-ation& and comment& .Comment on bot( po&iti-e and ne%ati-e a&pect& of t(e manufacture of *remi4e&0 3upplement& and Biolo%ical @eed Additi-e&+ Record e-idence &i%(ted and re-ie/ed0 &uc( a& 3O*&0 record&0 ob&er-ation&0 etc0 particularly /it( re&pect to non-conformance1 +

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