Comparison of Different Versions of Annex 2 EU Guide to GMP

7/30/2019 Comparison of Different Versions of Annex 2 EU Guide to GMP

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Comparison of Different Versions of Annex 2 EU Guide to GMP Part I (November 2012)

© 2012 Maas & Peither AG – GMP Publishing, Karlstrasse 2, 79650 Schopfheim, Germany, www.gmp-publishing.com Page 1/49

Manufacture of Biological MedicinalProducts for Human Use

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Manufacture of Biological MedicinalSubstances and Products for HumanUse

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Manufacture of Biological ActiveSubstances and Medicinal Productsfor Human Use

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Comments Maas & Peither

Scope Scope Scope

The methods employed in themanufacture of biological medicinalproducts are a critical factor in shapingthe appropriate regulatory control.Biological medicinal products can bedefined therefore largely by reference totheir method of manufacture. Biologicalmedicinal products prepared by thefollowing methods of manufacture will fallunder the scope of this annex (1).Biological medicinal productsmanufactured by these methods include:

vaccines, immunosera, antigens,hormones, cytokines, enzymes and otherproducts of fermentation (includingmonoclonal antibodies and productsderived from r-DNA).

The methods employed in themanufacture of biological edicinalsubstances and products are a criticalfactor in shaping the appropriateregulatory control. Biological medicinalsubstances and products can be definedtherefore largely by reference to theirmethod of manufacture.

This annex, along with several otherannexes of the Guide to GMP, providesguidance which supplements that in Part

I and in Part II of the Guide. There aretwo aspects to the scope of this annex:

The methods employed in themanufacture of biological activesubstances and biological medicinal products for human use ('biological activesubstances and medicinal products') area critical factor in shaping the appropriateregulatory control.Biological active substances andmedicinal products can be definedtherefore largely by reference to theirmethod of manufacture. This annexprovides guidance on the full range of

active substances and medicinalproducts defined as biological. This annex is divided into two main parts:a) Part A contains supplementaryguidance on the manufacture ofbiological active substances andmedicinal products, from control overseed lots and cell banks through tofinishing activities, and testing.b) Part B contains further guidance onselected types of biological activesubstances and medicinal products.This annex, along with several other

annexes of the Guide to GMP inEudraLex Volume 4, provides guidancewhich supplements that in Part I and inPart II of that Guide. There are twoaspects to the scope of this annex:

The scope for active substances and biological medicinal products for human use is now more precise.Additionally the concept of part A and B is already introduced earlier in the document.

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a) Microbial cultures, excluding thoseresulting from r-DNA techniques;

a) Stage of manufacture - for biologicalactive substances to the pointimmediately prior to their being renderedsterile, the primary guidance source isPart II. Guidance for the subsequentmanufacturing steps of biologicalproducts are covered in Part I. For sometypes of product (e.g. cell-basedproducts) all manufacturing steps need tobe conducted aseptically.

a) Stage of manufacture - for biologicalactive substances to the pointimmediately prior to their being renderedsterile, the primary guidance source isPart II. Guidance for the subsequentmanufacturing steps of biologicalproducts are covered in Part I.

The reference to aseptic manufactured active substances was withdrawn.

b) Microbial and cell cultures, includingthose resulting from recombinant DNA orhybridoma techniques;

b) Type of product - this annex providesguidance on the full range of medicinalsubstances and products defined asbiological.

b) Type of product - this annex providesguidance on the full range of medicinalproducts defined as biological.

Slight editorial changes.

c) Extraction from biological tissues These two aspects are shown in Table 1,it should be noted that this table isillustrative only and not meant to describethe precise scope.It should also be understood that in linewith the corresponding table in Part II ofthe Guide, the level of GMP increases indetail from early to later steps in themanufacture of biological substances butGMP principles should always beadhered to. The inclusion of some earlysteps of manufacture within the scope ofthe annex does not imply that those steps

These two aspects are shown in Table 1,it should be noted that this table isillustrative only and is not meant todescribe the precise scope. It should alsobe understood that in line with thecorresponding table in Part II ofEudraLex, Volume 4, the level of GMPincreases in detail from early to latersteps in the manufacture of biologicalactive substances but GMP principlesshould always be adhered to.Theinclusion of some early steps ofmanufacture within the scope of this

Only editorial changes and detailed definition for active substances.










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will be routinely subject to inspection bythe authorities.

Annex does not imply that those stepswill be routinely subject to inspection bythe authorities.

d) Propagation of live agents in embryosor animals (Not all of the aspects of thisannex may necessarily apply to productsin category a).

Although antibiotics are not included asbiological products, however wherebiological stages of manufacture occur,guidance in this Annex may be used.Guidance for medicinal products derivedfrom human blood or plasma is coveredin Annex 14 and for non-transgenic plant

products in Annex 7.

Antibiotics are not defined as biologicalmedicinal products, however wherebiological stages of manufacture occur,guidance in this Annex may be used.Guidance for medicinal products derivedfrom fractionated human blood or plasmais covered in Annex 14 of EudraLex,

Volume 4, and for non-transgenic plantproducts in Annex 7.


Note In drawing up this guidance, due consideration has been given to the general requirements for manufacturing establishments and control laboratories proposed by the WHO. The present guidance does not lay down detailed requirements for specific classes of biological products, and attention is therefore directed to other guidelines issued by the Committee for Proprietary Medicinal Products (CPMP), for example the note for guidance on monoclonal antibodies and the note for guidance on products of recombinant DNA technology (“The rules governing medicinal product in the European Community”, Volume 3).

The annex is divided into two main parts: In certain cases, other legislation isapplicable to the starting materials:










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a) Part A contains supplementaryguidance on the manufacture ofbiological medicinal substances andproducts, from control over seed lots andcell banks through to finishing activities,and testing.

(a) Tissue and cells used for industriallymanufactured products (such asmedicinal products): Directive2004/23/EC of the European Parliamentand of the Council of 31 March 2004 onsetting standards of quality and safety forthe donation, procurement, testing,processing, preservation, storage anddistribution of human tissues andcells,3and Commission Directive2006/17/EC of 8 February 2006

implementing Directive 2004/23/EC of theEuropean Parliament and of the Councilas regards certain technical requirementsfor the donation, procurement and testingof human tissues and cells4 cover onlytheir donation, procurement and testing.Such tissues and cells become thebiological active substances for severalbiological medicinal product types (e.gwhen ‘engineered’5) at which point GMPand other medicinal product legislationrequirements apply.

The reference to other regulatory requirements is newly incorporated.

b) Part B contains further guidance onselected types of biological medicinalsubstances and products. Themanufacture and control of geneticallymodified organisms must comply withlocal and national requirements.

(b) Where blood or blood componentsare used as starting materials foradvanced therapy medicinal products(ATMPs), Directive 2002/98/EC of theEuropean Parliament and of the Councilof 27 January 2003 setting standards of











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According to Directive 1998/81/EC oncontained use of genetically modifiedmicro-organisms, appropriatecontainment should be established andmaintained in facilities where anygenetically modified micro-organisms arehandled. Advice should be obtainedaccording to national legislation in orderto establish and maintain the appropriateBiological Safety Level. There should beno conflicts with GMP requirements.

quality and safety for the collection,testing, processing, storage anddistribution of human blood and bloodcomponents and amending Directive2001/83/EC6 and its CommissionDirectives provides the technicalrequirements7 for the selection of donorsand the collection and testing of bloodand blood components.

(c) The manufacture and control ofgenetically modified organisms needs tocomply with local and nationalrequirements. In accordance withDirective 2009/41/EC of the EuropeanParliament and of the Council of 6 May2009 on the contained use of geneticallymodified micro-organisms ,8 appropriatecontainment and other protectivemeasures shall be established andmaintained in facilities where anygenetically modified micro-organism are

handled. Advice should be obtainedaccording to national legislation in orderto establish and maintain the appropriateBiological Safety Level. There should beno conflicts with GMP requirements.











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Principle Principle Principle

The manufacture of biological medicinalproducts involves certain specificconsiderations arising from the nature ofthe products and the processes. The wayin which biological medicinal products areproduced, controlled and administeredmake some particular precautionsnecessary.

The manufacture of biological medicinalproducts involves certain specificconsiderations arising from the nature ofthe products and the processes. Theways in which biological medicinalproducts are manufactured, controlledand administered make some particularprecautions necessary.

The manufacture of biological medicinalactive substances and products involvescertain specific considerations arisingfrom the nature of the products and theprocesses. The ways in which biologicalmedicinal products are manufactured,controlled and administered make someparticular precautions necessary.

Detailed definition concerning active substances.

Unlike conventional medicinal products,

which are reproduced using chemical andphysical techniques capable of a highdegree of consistency, the production ofbiological medicinal products involvesbiological processes and materials, suchas cultivation of cells or extraction ofmaterial from living organisms. Thesebiological processes may display inherentvariability, so that the range and nature ofby-products are variable. Moreover, thematerials used in these cultivationprocesses provide good substrates forgrowth of microbial contaminants.


which are manufactured using chemicaland physical techniques capable of ahigh degree of consistency, themanufacture of biological medicinalsubstances and products involvesbiological processes and materials, suchas cultivation of cells or extraction ofmaterial from living organisms. Thesebiological processes may display inherentvariability, so that the range and nature ofby-products may be variable. As a result,quality risk management principles areparticularly important for this class ofmaterials and should be used to developtheir control strategy across all stages ofmanufacture so as to minimise variabilityand to reduce the opportunity forcontamination and cross-contamination.


which are manufactured using chemicaland physical techniques capable of ahigh degree of consistency, themanufacture of biological active substances and medicinal productsinvolves biological processes andmaterials, such as cultivation of cells orextraction from living organisms. Thesebiological processes may display inherentvariability, so that the range and nature ofby-products may be variable. As a result,quality risk management (QRM) principles are particularly important forthis class of materials and should beused to develop the control strategyacross all stages of manufacture so as tominimise variability and to reduce theopportunity for contamination and cross-contamination.

Detailed definition concerning

active substances.










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Control of biological medicinal productsusually involves biological analyticaltechniques which have a greatervariability than physico-chemicaldeterminations. In-process controlstherefore take on a great importance inthe manufacture of biological medicinalproducts.

Since materials and processingconditions used in cultivation processesare designed to provide conditions for thegrowth of specific cells andmicroorganisms, this provides extraneousmicrobial contaminants the opportunity togrow. In addition, many products arelimited in their ability to withstand a widerange of purification techniquesparticularly those designed to inactivateor remove adventitious viral

contaminants. The design of theprocesses, equipment, facilities, utilities,the conditions of preparation and additionof buffers and reagents, and training ofthe operators are key considerations tominimise such contamination events.

Since materials and processingconditions used in cultivation processesare designed to provide conditions for thegrowth of specific cells andmicroorganisms, this provides extraneousmicrobial contaminants the opportunity togrow. In addition, many products arelimited in their ability to withstand a widerange of purification techniquesparticularly those designed to inactivateor remove adventitious viral

contaminants. The design of theprocesses, equipment, facilities, utilities,the conditions of preparation and additionof buffers and reagents, sampling andtraining of the operators are keyconsiderations to minimise suchcontamination events.


Specifications related to GMP (such asthose in Pharmacopoeial monographs,Marketing Authorisation (MA), andClinical Trial Authorisation, (CTA)) will

dictate whether and to what stagesubstances and materials can have adefined level of bioburden or need to besterile. For active substances whosespecification allows a managed level ofbioburden – see guidance in Part II.

Specifications related to products (suchas those in Pharmacopoeial monographs,Marketing Authorisation (MA), andClinical Trial Authorisation, (CTA)) will

dictate whether and to what stagesubstances and materials can have adefined level of bioburden or need to besterile. Similarly, manufacturing must beconsistent with other specifications setout in the MA or CTA guidance (e.g.number of generations (doublings,

More detailed definition concerning specifications than compared to the draft version.










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passages) between the seed lot or cellbank).

For biological materials that cannot besterilised (e.g. by filtration), processingmust be conducted aseptically tominimise the introduction ofcontaminants.The application of appropriateenvironmental controls and monitoringand, wherever feasible, in-situ cleaningand sterilization systems together withthe use of closed systems cansignificantly reduce the risk of accidentalcontamination and cross-contamination.

For biological materials that cannot besterilized (e.g. by filtration), processingmust be conducted aseptically tominimise the introduction ofcontaminants. Where they exist, CHMPguidance documents should be consultedon the validation of specificmanufacturing methods, e.g. virusremoval or inactivation. The application ofappropriate environmental controls andmonitoring and, wherever feasible, in-situcleaning and sterilization systemstogether with the use of closed systemscan significantly reduce the risk ofaccidental contamination and cross-contamination.

Additional reference to CHMP guidance documents which have to be followed.

Control usually involves biologicalanalytical techniques, which typicallyhave a greater variability than physico-chemical determinations. A robustmanufacturing process is thereforecrucial and in-process controls take on aparticular importance in the manufactureof biological medicinal substances andproducts.

Control usually involves biologicalanalytical techniques, which typicallyhave a greater variability than physico-chemical determinations. A robustmanufacturing process is thereforecrucial and in-process controls take on aparticular importance in the manufactureof biological active substances andmedicinal products.











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Biological medicinal products whichincorporate human tissues or cells, suchas certain Advanced Therapy MedicinalProducts (ATMPs) must comply with therequirements of Directive 2004/23/ECand Directive 2006/17/EC for thedonation, procurement and testingstages. In line with Commission Directive2006/86/EC collection and testing mustbe done in accordance with an

appropriate quality system for whichstandards and specifications are definedin its Annex7.

Furthermore, the requirements ofDirective 2006/86/EC on traceability and

serious adverse reactions and seriousadverse events notifications apply fromthe donor to the recipient. Tissueestablishments supplying such materialsare required to have a system in place totrace all substances coming into contactwith the cells or tissues, while

Biological medicinal products whichincorporate human tissues or cells, suchas certain ATMPs must comply with therequirements of Directive 2004/23/ECand Commission Directive 2006/17/EC.

In line with Commission Directive2006/86/EC of 24 October 2006implementing Directive 2004/23/EC of theEuropean Parliament and of the Council

as regards traceability requirements,notification of serious adverse reactionsand events and certain technicalrequirements for the coding, processing,preservation, storage and distribution ofhuman tissues and cells,15 collection andtesting must be done in accordance withan appropriate quality system for whichstandards and specifications are definedin its Annex16. Furthermore, therequirements of Commission Directive2006/86/ EC of 24 October 2006implementing Directive 2004/23/EC of the

European Parliament and of the Councilas regards traceability requirements,notification of serious adverse reactionsand events and certain technicalrequirements for the coding, processing,preservation, storage and distribution ofhuman tissues and cells,17on traceability

In this section the references and the scope are more detailed.










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maintaining donor and patient confidentiality.

apply from the donor (while maintainingdonor confidentiality) through stagesapplicable at the Tissue Establishmentand then continue under medicineslegislation through to the institution wherethe product is used.

Biological medicinal substances andproducts must comply with the latestversion of the Note for Guidance onMinimising the Risk of TransmittingAnimal Spongiform EncephalopathyAgents via Human and VeterinaryMedicinal Products.

Biological active substances andmedicinal products must comply with thelatest version of the Note for Guidance onMinimising the Risk of TransmittingAnimal Spongiform Encephalopathy(TSE) Agents via Human and VeterinaryMedicinal Products.


Part A General Guidance Part A General Guidance

Personnel Personnel Personnel

1. All personnel (including thoseconcerned with cleaning, maintenance orquality control) employed in areas where

biological medicinal products aremanufactured should receive additionaltraining specific to the productsmanufactured and to their work.Personnel should be given relevantinformation and training in hygiene andmicrobiology.

1. Personnel (including those concernedwith cleaning, maintenance or qualitycontrol) employed in areas where

biological medicinal products aremanufactured and tested should receivetraining, and periodic retraining, specificto the products manufactured to theirwork, including any specific securitymeasures to protect product, personneland the environment.

1. Personnel (including those concernedwith cleaning, maintenance or qualitycontrol) employed in areas where

biological active substances and productsare manufactured and tested shouldreceive training, and periodic retraining,specific to the products manufactured totheir work, including any specific securitymeasures to protect product, personneland the environment.

Slight editorial changes (active subtances).










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2. Persons responsible for productionand quality control should have anadequate background in relevantscientific disciplines, such asbacteriology, biology, biometry,chemistry, medicine, pharmacy,pharmacology, virology, immunology andveterinary medicine, together withsufficient practical experience to enablethem to exercise their managementfunction for the process concerned.

2. The health status of personnel mayhave to be taken into consideration forproduct safety. Where necessary,personnel engaged in production,maintenance, testing and animal care(and inspections) should be vaccinatedwith appropriate specific vaccines andhave regular health checks.

2. The health status of personnel shouldbe taken into consideration for productsafety. Where necessary, personnelengaged in production, maintenance,testing and animal care (and inspections)should be vaccinated with appropriatespecific vaccines and have regular healthchecks.

“Should” is a stronger requirement as “may have”.

3. The immunological status of personnelmay have to be taken into considerationfor product safety. All personnel engagedin production, maintenance, testing andanimal care (and inspectors) should bevaccinated where necessary withappropriate specific vaccines and haveregular health checks. Apart from theobvious problem of exposure of staff toinfectious agents, potent toxins orallergens, it is necessary to avoid the riskof contamination of a production batch

with infectious agents. Visitors shouldgenerally be excluded from productionareas.

3. Any changes in the health status ofpersonnel, which could adversely affectthe quality of the product, shouldpreclude work in the production area.Production of BCG vaccine andtuberculin products should be restrictedto staff who are carefully monitored byregular checks of immunological status orchest X-ray. Medical advice should besought for personnel involved with liveand genetically modified organisms.

3. Any changes in the health status ofpersonnel, which could adversely affectthe quality of the product, shouldpreclude work in the production area andappropriate records kept. Production ofBCG vaccine and tuberculin productsshould be restricted to staff who arecarefully monitored by regular checks ofimmunological status or chest X-ray.Health monitoring of staff should becommensurate with the risk, medicaladvice should be sought for personnel

involved with hazardous organisms.

Requirement of appropriate records is introduced as well as more details on the monitoring of personal.

4. Any changes in the immunologicalstatus of personnel which could

4. Where required to minimise theopportunity for cross-contamination,

4. Where required to minimise theopportunity for cross-contamination,











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adversely affect the quality of the productshould preclude work in the productionarea. Production of BCG vaccine andtuberculin products should be restrictedto staff who are carefully monitored byregular checks of immunological status orchest X-ray.

restrictions on the movement of allpersonnel (including QC, maintenanceand cleaning staff) should be controlledon the basis of quality r isk managementprinciples.In general, during the course ofa working day, personnel should not passfrom areas where exposure to liveorganisms, genetically modifiedorganisms, toxins or animals to areaswhere other products, inactivated

products or different organisms arehandled. If such passage is unavoidable,the contamination control measuresshould be based on quality riskmanagement principles.

restrictions on the movement of allpersonnel (including quality control (QC),maintenance and cleaning staff) shouldbe controlled on the basis of QRMprinciples.In general, personnel should not passfrom areas where exposure to live micro-organisms, genetically modifiedorganisms, toxins or animals to areaswhere other products, inactivatedproducts or different organisms are

handled. If such passage is unavoidable,the contamination control measuresshould be based on QRM principles.

5. In the course of a working day,personnel should not pass from areaswhere exposure to live organisms oranimals is possible to areas where otherproducts or different organisms arehandled. If such passage is unavoidable,clearly defined decontamination

measures, including change of clothingand shoes and, where necessary,showering should be followed by staffinvolved in any such production.










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Premises and equipment Premises and equipment Premises and equipment

6. The degree of environmental control ofparticulate and microbial contamination ofthe production premises should beadapted to the product and theproduction step, bearing in mind the levelof contamination of the starting materialsand the risk to the finished product.

5. As part of the control strategy, thedegree of environmental control ofparticulate and microbial contamination ofthe production premises should beadapted to the product and theproduction step, bearing in mind the levelof contamination of the starting materialsand the risks to the product.

The environmental monitoringprogramme should be supplemented bythe inclusion of methods to detect thepresence of specific microorganisms (i.e.host organism, yeast, moulds,anaerobes, etc) where indicated by riskanalysis.

5. As part of the control strategy, thedegree of environmental control ofparticulate and microbial contamination ofthe production premises should beadapted to the active substance,intermediate or finished product and theproduction step, bearing in mind thepotential level of contamination of thestarting materials and the risks to theproduct. The environmental monitoringprogramme should be supplemented bythe inclusion of methods to detect thepresence of specific microorganisms (i.e.host organism, yeast, moulds,anaerobes, etc) where indicated by theQRM process.

More details concerning monitoring which are also applicable on active substances, intermediates and finished products.

7. The risk of cross-contaminationbetween biological medicinal products,especially during those stages of themanufacturing process in which liveorganisms are used, may requireadditional precautions with respect tofacilities and equipment, uch as the useof dedicated facilities and equipment,production on a campaign basis and theuse of closed systems. The nature of the

6. Manufacturing facilities, processes andenvironmental classifications should bedesigned to prevent the extraneouscontamination of products. The use ofdisposable technologies should also beconsidered. Prevention of contamination is moreappropriate than detection and removal,although contamination is likely tobecome evident during processes such

6. Manufacturing and storage facilities,processes and environmentalclassifications should be designed toprevent the extraneous contamination ofproducts.

Prevention of contamination is moreappropriate than detection and removal,although contamination is likely to

“Storage” is added to the scope. Additional slight editorial changes.










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product as well as the equipment usedwill determine the level of segregationneeded to avoid cross-contamination.

as fermentation and cell culture. Whereopen processes (e.g. cell bank or seedlot establishment or expansion) or asepticprocesses (e.g. additions of supplements,media, buffers, gasses, manipulationsduring the manufacture of ATMPs) areused, measures should be put in place,including engineering and environmentalcontrols on the basis of quality riskmanagement principles. These riskmanagement principles should take into

account the principles and guidance inthe appropriate sections of Annex 1 whenselecting environmental classificationcascades and associated controls.

become evident during processes suchas fermentation and cell culture. Whereprocesses are not closed and there istherefore exposure of the product to theimmediate room environment (e.g. duringadditions of supplements, media, buffers,gasses, manipulations during themanufacture of ATMPs) controlmeasures should be put in place,including engineering and environmentalcontrols on the basis of QRM principles.

These QRM principles should take intoaccount the principles and guidance fromthe appropriate sections of Annex 118 toEudraLex, Volume 4, when selectingenvironmental classification cascadesand associated controls.

8. In principle, dedicated facilities shouldbe used for the production of BCGvaccine and for the handling of liveorganisms used in production oftuberculin products.

7. Dedicated production areas should beused for the production of BCG vaccine,for the handling of live organisms used inproduction of tuberculin products and forlive organisms of BSL 3 or 4.

7. Dedicated production areas should beused for the handling of live cells capableof persistence in the manufacturingenvironment. Dedicated production areashould be used for the manufacture ofpathogenic organisms (i.e. Biosafety level3 or 4).

Newly written section.

9. Dedicated facilities should be used forthe handling of Bacillus anthracis, ofClostridium botulinum and of Clostridium

8. In general dedicated production areasshould be used for the handling of livecells and organisms (e.g. for ATMP

This section was skipped.










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tetani until the inactivation process isaccomplished.

production and vaccine production) andspore forming organisms such as Bacillusanthracis, Clostridium botulinum andClostridium tetani until the inactivationprocess is accomplished. Similarly, forkilled vaccines and toxoids, parallelprocessing should only be performedafter inactivation of the culture or afterdetoxification.

10. Production on a campaign basis maybe acceptable for other spore formingorganisms provided that the facilities arededicated to this group of products andnot more than one product is processedat any one time.

9. Manufacture in a multiproduct facilitymay be acceptable where the following,or equivalent, considerations andmeasures are shown to be an effectivepart of the control strategy to preventcross-contamination:

8. Manufacture in a multi-product facilitymay be acceptable where the following,or equivalent (as appropriate to theproduct types involved) considerationsand measures are part of an effectivecontrol strategy to prevent cross-contamination:


11. Simultaneous production in the samearea using closed systems ofbiofermenters may be acceptable forproducts such as monoclonal antibodiesand products prepared by DNAtechniques.

(a) Knowledge of key characteristics of allcells, organisms and any adventitiousagents (e.g. pathogenicity, detectability,persistence, susceptibility to inactivation)within the same facility.

(a) Knowledge of key characteristics of allcells, organisms and any adventitiousagents (e.g. pathogenicity, detectability,persistence, susceptibility to inactivation)within the same facility.

No changes compared to the draft.

12. Processing steps after harvestingmay be carried out simultaneously in thesame production area provided thatadequate precautions are taken toprevent cross contamination. For killed

(b) Where production is characterised bymultiple small batches from differentstarting materials (e.g. cell-basedproducts) factors such as the healthstatus of donors and the risk of total loss

Previously this section was draft section (12)










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vaccines and toxoids, such parallelprocessing should only be performedafter inactivation of the culture or afterdetoxification.

of product from or for specific patientsshould be taken into account whenconsidering the acceptance of concurrentworking during development of thecontrol strategy.

13. Positive pressure areas should beused to process sterile products butnegative pressure in specific areas atpoint of exposure of pathogens isacceptable for containment reasons.Where negative pressure areas or safetycabinets are used for aseptic processingof pathogens, they should be surroundedby a positive pressure sterile zone.

(b) Live organisms and spores areprevented from entering non-relatedareas or equipment by addressing allpotential routes of cross-contaminationand utilizing single use components andengineering measures such as closedsystems.

(c) Live organisms and spores areprevented from entering non-relatedareas or equipment by addressing allpotential routes of cross-contaminationand utilizing single use components andengineering measures such as closedsystems.


14. Air filtration units should be specific tothe processing area concerned andrecirculation of air should not occur f romareas handling live pathogenicorganisms.

(c) Control measures to remove theorganisms and spores before thesubsequent manufacture of otherproducts. Cleaning and decontaminationfor the organisms and spores should bevalidated including the HVAC system.

(d) Control measures to remove theorganisms and spores before thesubsequent manufacture of otherproducts, these control measures shouldalso take the heating, ventilation and airconditioning (HVAC) system into account. Cleaning and decontamination for the

organisms and spores should bevalidated.

The scope for HVAC is defined more precisely

15. The layout and design of productionareas and equipment should permit

(d) Environmental monitoring specific forthe organism is conducted in adjacent

(e) Environmental monitoring specific forthe micro-organism being manufactured,

In this section the microbiological requirements










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effective cleaning and decontamination(e.g. by fumigation). The adequacy ofcleaning and decontaminationprocedures should be validated.

areas during manufacture and aftercompletion of cleaning anddecontamination.

Attention should also be given to risksarising with use of certain monitoringequipment (e.g. airborne particlemonitoring) in areas handling live and/or

spore forming organisms.

where the micro-organisms are capableof persistence in the manufacturingenvironment and where methods areavailable, is conducted in adjacent areasduring manufacture and after completionof cleaning and decontamination.Attention should also be given to risksarising with use of certain monitoringequipment (e.g. airborne particlemonitoring) in areas handling live and/orspore forming organisms.

are defined more precisely.

16. Equipment used during handling oflive organisms should be designed tomaintain cultures in a pure state anduncontaminated by external sourcesduring processing.

(e) Products, equipment, ancillaryequipment (e.g. for calibration andvalidation) and disposable items are onlymoved within and removed from suchareas in a manner that preventscontamination of other areas, otherproducts and different product stages(e.g. prevent contamination of inactivatedor toxoided products with non-inactivatedproducts).

(f) Products, equipment, ancillaryequipment (e.g. for calibration andvalidation) and disposable items are onlymoved within and removed from suchareas in a manner that preventscontamination of other areas, otherproducts and different product stages(e.g. prevent contamination of inactivatedor toxoided products with non-inactivatedproducts).


17. Pipework systems, valves and ventfilters should be properly designed tofacilitate cleaning and sterilisation. Theuse of ‘clean in place’ and ‘sterilise inplace’ systems should be encouraged.

(f) Campaign-based manufacturing. (g) Campaign-based manufacturing. No changes compared to the draft.










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Valves on fermentation vessels should becompletely steam sterilisable. Air ventfilters should be hydrophobic andvalidated for their scheduled life span.

18. Primary containment should bedesigned and tested to demonstratefreedom from leakage risk.

10. For finishing operations, therequirement for dedicated facilities willdepend on the above considerationstogether with additional considerationssuch as the specific needs of thebiological product and on the

characteristics of other products,including any non-biological products, inthe same facility. Other control measuresfor finishing operations may include theneed for specific addition sequences,mixing speeds, time and temperaturecontrols, limits on exposure to light andcontainment and cleaning procedures inthe event of spillages.

9. For finishing (secondary) operations,the need for dedicated facilities willdepend on consideration of the abovetogether with additional considerationssuch as the specific needs of thebiological medicinal product and on thecharacteristics of other products,including any non-biological products, inthe same facility. Other control measuresfor finishing operations may include theneed for specific addition sequences,mixing speeds, time and temperaturecontrols, limits on exposure to light andcontainment and cleaning procedures inthe event of spillages.


19. Effluents which may containpathogenic micro-organisms should be

effectively decontaminated.

11. The measures and proceduresnecessary for containment (i.e. for

environment and operator safety) shouldnot conflict with those for product safety.

10. The measures and proceduresnecessary for containment (i.e. for

environment and operator safety) shouldnot conflict with those for product quality.


20. Due to the variability of biologicalproducts or processes, some additives or

12. Where production is characterised bymultiple small batches from different

This section is now sec. 8 (b).










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ingredients have tobe measured or weighed during theproduction process (e.g. buffers). Inthese cases, smallstocks of these substances may be keptin the production area.

starting materials (e.g. cell-basedproducts) factors such as the healthstatus of donors and the risk of total lossof product from and/or for specificpatients should be taken into accountwhen considering the acceptance ofconcurrent working during developmentof the control strategy.

13. Air handling units should be designedconstructed and maintained to minimise

the risk of cross-contamination betweendifferent manufacturing areas and mayneed to be specific for an area.Consideration, based on quality riskmanagement principles, should be givento the use of single pass air systems.

11. Air handling units should bedesigned, constructed and maintained to

minimise the risk of cross-contaminationbetween different manufacturing areasand may need to be specific for an area.Consideration, based on QRM principles,should be given to the use of single passair systems.


14. Positive pressure areas should beused to process sterile products butnegative pressure in specific areas at thepoint of exposure of pathogens isacceptable for containment reasons.Where negative pressure areas or safety

cabinets are used for aseptic processingof materials with particular risks (e.g.pathogens) they should be surrounded bya positive pressure clean zone ofappropriate grade.

12. Positive pressure areas should beused to process sterile products butnegative pressure in specific areas at thepoint of exposure of pathogens isacceptable for containment reasons.Where negative pressure areas or safety

cabinets are used for aseptic processingof materials with particular risks (e.g.pathogens) they should be surrounded bya positive pressure clean zone ofappropriate grade. These pressurecascades should be clearly defined and

More detailed definition for pressure cascades.










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continuously monitored with appropriatealarm settings.

15. Equipment used during handling oflive organisms and cells, including thosefor sampling, should be designed toprevent any contamination duringprocessing.

13. Equipment used during handling oflive organisms and cells, including thosefor sampling, should be designed toprevent any contamination duringprocessing.


16. Primary containment should be

designed and periodically tested todemonstrate absence of leakage.

14. Primary containment should be

designed and periodically tested toensure the prevention of escape ofbiological agents into the immediateworking environment.

More detailed defintion in the

the final version.

17. The use of 'clean in place' andsterilization in place (e.g. ‘steam inplace’) systems should be used wherepossible. Valves on fermentation vesselsshould be completely steam sterilisable.

15. The use of 'clean in place' and ‘steamin place’ (‘sterilisation in place’) systemsshould be used where possible. Valveson fermentation vessels should becompletely steam sterilisable.


18. Air vent filters should be hydrophobicand validated for their scheduled life spanwith integrity testing at appropriateintervals.

16. Air vent filters should be hydrophobicand validated for their scheduled life spanwith integrity testing at appropriateintervals based on appropriate QRMprinciples.

Reference to quality risk management.










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19. Drainage systems must be designedso that effluents can be effectivelyneutralised or decontaminated tominimise the risk of cross-contaminationand, where required by local regulation, minimise the risk of contamination of theexternal environment according to therisk associated with the biohazardousnature of waste materials.

17. Drainage systems must be designedso that effluents can be effectivelyneutralised or decontaminated tominimise the risk of cross-contamination.Local regulation must be complied with to minimise the risk of contamination of theexternal environment according to therisk associated with the biohazardousnature of waste materials.


20. Due to the variability of biological

products or processes, relevant/criticaladditives or ingredients have to bemeasured or weighed during theproduction process. In these cases,stocks of these substances may be keptin the production area for a specifiedduration based on defined criteria suchas for the duration of manufacture of thebatch or of the campaign.

18. Due to the variability of biological

products or manufacturing processes,relevant/critical raw materials (such asculture media and buffers) have to bemeasured or weighed during theproduction process. In these cases, smallstocks of these raw materials may bekept in the production area for a specifiedduration based on defined criteria suchas for the duration of manufacture of thebatch or of the campaign.

More detailed defintions

compared to the draft.

Animal quarters and care Animals Animals

21. Animals are used for the manufactureof a number of biological products, forexample polio vaccine (monkeys), snakeantivenoms (horses and goats), rabiesvaccine (rabbits, mice and hamsters) andserum gonadotropin (horses). In addition,

A wide range of animal species are usedin the manufacture of a number ofbiological medicinal products or startingmaterials. These can be divided into 2broad types of sources:(a) Live groups, herds, flocks: examples

19. A wide range of animal species areused in the manufacture of a number ofbiological medicinal products. These canbe divided into 2 broad types of sources:(a) Live groups, herds, flocks: examplesinclude polio vaccine (monkeys),











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animals may also be used in the qualitycontrol of most sera and vaccines, e.g.pertussis vaccine (mice), pyrogenicity(rabbits), BCG vaccine (guinea-pigs).

include polio vaccine (monkeys),immunosera to snake venoms andtetanus (horses, sheep and goats),allergens (cats), rabies vaccine (rabbits,mice and hamsters), transgenic products(goats, cattle).(b) Animal tissues and cells derived post-mortem and from establishments such asabattoirs: examples include xenogeneiccells from animal tissues and cells,feeder cells to support the growth ofsome ATMPs, abattoir sources forenzymes, anticoagulants and hormones(sheep and pigs).In addition, animals may also be used inquality control either in generic assays,e.g. pyrogenicity, or specific potencyassays, e.g. pertussis vaccine (mice),pyrogenicity (rabbits),BCG vaccine (guinea-pigs).

immunosera to snake venoms andtetanus (horses, sheep and goats),allergens (cats), rabies vaccine (rabbits,mice and hamsters), transgenic products(goats, cattle).(b) Animal tissues and cells derived post-mortem and from establishments such asabattoirs: examples include xenogeneiccells from animal tissues and cells,feeder cells to support the growth ofsome ATMPs, abattoir sources forenzymes, anticoagulants and hormones(sheep and pigs).In addition, animals may also be used inquality control either in generic assays,e.g. pyrogenicity, or specific potencyassays, e.g. pertussis vaccine (mice),pyrogenicity (rabbits), BCG vaccine(guinea-pigs).

21. In addition to compliance with TSEregulations, other adventitious agentsthat are of concern (zoonotic diseases,diseases of source animals) should bemonitored by an ongoing healthprogramme and recorded. Specialistadvice should be obtained in establishingsuch programmes. Instances of ill-healthoccurring in the source animals should beinvestigated with respect to their

20. In addition to compliance with TSEregulations, other adventitious agentsthat are of concern (zoonotic diseases,diseases of source animals) should bemonitored by an ongoing healthprogramme and recorded. Specialistadvice should be obtained in establishingsuch programmes. Instances of ill-healthoccurring in the source /donor animalsshould be investigated with respect to











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suitability and the suitability of in-contactanimals for continued use (inmanufacture, as sources of startingmaterials, in quality control and safetytesting), the decisions must bedocumented. A look-back procedureshould be in place which informs thedecision making process on thecontinued suitability of the medicinalsubstance(s) or product(s) in which thematerials have been used orincorporated. This decision-makingprocess may include the re-testing ofretained samples from previouscollections from the same donor (whereapplicable) to establish the last negativedonation. The withdrawal period oftherapeutic agents used to treat sourceanimals must be documented and usedto determine the removal of thoseanimals from the programme for definedperiods.

their suitability and the suitability of in-contact animals for continued use (inmanufacture, as sources of starting andraw materials, in quality control andsafety testing), the decisions must bedocumented. A look-back procedureshould be in place which informs thedecision-making process on thecontinued suitability of the biologicalactive substance or medicinal product inwhich the animal sourced starting or rawmaterials have been used orincorporated. This decision-makingprocess may include the re-testing ofretained samples from previouscollections from the same donor animal(where applicable) to establish the lastnegative donation. The withdrawal periodof therapeutic agents used to treatsource /donor animals must bedocumented and used to determine theremoval of those animals from theprogramme for defined periods.

22. Particular care should be taken toprevent and monitor infections in thesource / donor animals. Measures shouldinclude the sourcing, facilities,husbandry, biosecurity procedures,testing regimes, control of bedding and

21. Particular care should be taken toprevent and monitor infections in thesource/donor animals. Measures shouldinclude the sourcing, facilities,husbandry, biosecurity procedures,testing regimes, control of bedding and











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feed materials. This is of specialrelevance to specified pathogen freeanimals where PhEur monographrequirements must be met. Housing andhealth monitoring should be defined forother categories of animals (e.g. healthyflocks or herds).

feed materials. This is of specialrelevance to specified pathogen freeanimals where PhEur monographrequirements must be met. Housing andhealth monitoring should be defined forother categories of animals (e.g. healthyflocks or herds).

23. For products manufactured fromtransgenic animals, traceability should bemaintained in the creation of suchanimals from the source animals.

22. For products manufactured fromtransgenic animals, traceability should bemaintained in the creation of suchanimals from the source animals.


22. General requirements for animalquarters, care and quarantine are laiddown in Directive 86/609/EEC2. Quartersfor animals used in production andcontrol of biological products should beseparated from production and controlareas. The health status of animals f romwhich some starting materials are derivedand of those used for quality control andsafety testing should be monitored andrecorded. Staff employed in such areasmust be provided with special clothing

and changing facilities. Where monkeysare used for the production or qualitycontrol of biological medicinal products,special consideration is required as laiddown in the current WHO Requirementsfor Biological Substances n°7.

24. Note should be taken of Directiverequirements for animal quarters, careand quarantine. Housing for animalsused in production and control ofbiological products should be separatedfrom production and control areas.

23. Note should be taken of CouncilDirective 86/609/EEC on theapproximation of laws, regulations andadministrative provisions of the MemberStates regarding the protection ofanimals used for experimental and otherscientific purposes as regardsrequirements for animal quarters, careand quarantine. Housing for animalsused in production and control ofbiological active substances andmedicinal products should be separated

from production and control areas.

More detailed definitons regarding regulatory requirements.










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25. For different animal species, keycriteria should be defined, monitored, andrecorded. These may include age, weightand health status of the animals.

24. For different animal species, keycriteria should be defined, monitored, andrecorded. These may include age, weightand health status of the animals.


26. Animals, biological agents, and testscarried out should be the subject of anidentification system to prevent any riskof confusion and to control all identifiedhazards.

25. Animals, biological agents, and testscarried out should be the subject of anidentification system to prevent any riskof confusion and to control all identifiedhazards.


Documentation Documentation Documentation

23. Specifications for biological startingmaterials may need additionaldocumentation on the source, origin,method of manufacture and controlsapplied, particularly microbiologicalcontrols.

27. Specifications for biological startingmaterials may need additionaldocumentation on the source, origin,distribution chain, method ofmanufacture, and controls applied,particularly microbiological controls.

26. Starting and raw materials may needadditional documentation on the source,origin, distribution chain, method ofmanufacture, and controls applied, toassure an appropriate level of controlincluding their microbiological quality.

More detailed definition of “particularly”.

24. Specifications are routinely requiredfor intermediate and bulk biological

medicinal products.

28. Some product types may requirespecific definition of what materials

constitutes a batch, particularly somaticcells in the context of ATMPs. Forautologous and donor-matchedsituations, the manufactured productshould be viewed as a batch.

27. Some product types may requirespecific definition of what materials

constitutes a batch, particularly somaticcells in the context of ATMPs. Forautologous and donor-matchedsituations, the manufactured productshould be viewed as a batch.











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29. Where human cell or tissue donorsare used, full traceability is required fromstarting and raw materials, including allsubstances coming into contact with thecells or tissues through to confirmation ofthe receipt of the products at the point ofuse whilst maintaining the privacy ofindividuals and confidentiality of healthrelated information.Particular care should be taken tomaintain the traceability of products forspecial use cases, such as donor-matched cells.

Directives 2002/98/EC and 2005/61/ECapply to blood components when theyare used as supportive or raw material inthe manufacturing process of medicinalproducts. For ATMPs, traceabilityrequirement regarding human cellsincluding haematopoietic cells mustcomply with the principles laid down in

Directives 2004/23/EC and 2006/86/EC.

28. Where human cell or tissue donorsare used, full traceability is required fromstarting and raw materials, including allsubstances coming into contact with thecells or tissues through to confirmation ofthe receipt of the products at the point ofuse whilst maintaining the privacy ofindividuals and confidentiality of healthrelated information. Traceability recordsmust be retained for 30 years after theexpiry date of the medicinal product.Particular care should be taken tomaintain the traceability of medicinalproducts for special use cases, such asdonor-matched cells. Directives 2002/98/EC and CommissionDirective 2005/61/EC of 30 September2005 implementing Directive 2002/98/ECof the European Parliament and of theCouncil as regards traceabilityrequirements and notification of seriousadverse reactions and events apply toblood components when they are usedas starting or raw materials in the

manufacturing process of medicinalproducts. For ATMPs, traceabilityrequirement regarding human cellsincluding haematopoietic cells mustcomply with the principles laid down inDirectives 2004/23/EC and 2006/86/EC.The arrangements necessary to achieve

A traceability of 30 years after the expiry date must be ensured. (See sec. 30 in the draft). Reference to detailed regulatory references.










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the traceability and retention periodshould be incorporated into technicalagreements between the responsibleparties.

30. For ATMPs, traceability records mustbe retained by the MA Holder for aminimum of 30 years after the expiry dateof the product (Article 15 of Regulation1394/ 2007). The arrangementsnecessary to achieve this retention periodshould be incorporated into technical

agreements between the responsibleparties.

This section of the draft is incorporated in sec. 28 of the final version.

Production Production Production

31. Given the variability inherent in manybiological substances and products,steps to increase process robustnessthereby reducing process variability andenhancing reproducibility should beconsidered at the different stages of theproduct lifecycle such as process designand should be reassessed during Product

Quality Reviews.

29. Given the variability inherent in manybiological active substances andmedicinal products, steps to increaseprocess robustness thereby reducingprocess variability and enhancingreproducibility at the different stages ofthe product lifecycle such as processdesign should be reassessed during

Product Quality Reviews.


32. Since cultivation conditions, mediaand reagents are designed to promotethe growth of cells or microbialorganisms, typically in an axenic state,

30. Since cultivation conditions, mediaand reagents are designed to promotethe growth of cells or microbialorganisms, typically in an axenic state,











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particular attention should be paid in thecontrol strategy to ensure there arerobust steps that prevent or minimise theoccurrence of unwanted bioburden andassociated metabolites and endotoxins.For cell based advanced therapyproducts where production batches arefrequently small the risk of crosscontamination between cell preparationsfrom different donors with various healthstatus should be controlled under definedprocedures and requirements.

particular attention should be paid in thecontrol strategy to ensure there arerobust steps that prevent or minimise theoccurrence of unwanted bioburden andassociated metabolites and endotoxins.For cell based ATMPs where productionbatches are frequently small the risk ofcross-contamination between cellpreparations from different donors withvarious health status should be controlledunder defined procedures andrequirements.

Starting materials Starting and raw materials Starting and raw materials

25. The source, origin and suitability ofstarting materials should be clearlydefined. Where the necessary tests takea long time, it may be permissible toprocess starting materials before theresults of the tests are available. In suchcases, release of a finished product isconditional on satisfactory results ofthese tests.

33. The source, origin and suitability ofbiological starting materials should beclearly defined.

Where the necessary tests take a longtime, it may be permissible to processstarting materials before the results of the

tests are available.

In such cases, release of a finished

31. The source, origin and suitability ofbiological starting and raw materials (e.g.cryoprotectants, feeder cells, reagents,culture media, buffers, serum, enzymes,cytokines, growth factors) should beclearly defined. Where the necessarytests take a long time, it may bepermissible to process starting materialsbefore the results of the tests are

available, the risk of using a potentiallyfailed material and its potential impact onother batches should be clearlyunderstood and assessed under theprinciples of QRM. In such cases, release of a finished

In the final versio examples as well as quality risk management were incorporated.










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product is conditional on satisfactoryresults of these tests. The identification ofall starting materials should be incompliance with the requirementsappropriate to its stage of manufacture.For biological medicinal products furtherguidance can be found in Part I andAnnex 8 and for biological substances inPart II. For cell-based ATMPs, sterilitytests should be conducted on antibiotic-free cultures of cells or cell banks toprovide evidence for absence of bacterialand fungal contamination and considerthe detection of fastidious organisms.

product is conditional on satisfactoryresults of these tests. The identification ofall starting materials should be incompliance with the requirementsappropriate to its stage of manufacture.For biological medicinal products furtherguidance can be found in Part I andAnnex 8 and for biological activesubstances in Part II.

34. The risk of contamination of startingmaterials during their passage along thesupply chain must be assessed, withparticular emphasis on TSE. Materialsthat come into direct contact withmanufacturing equipment or the product(such as media used in media fillexperiments and lubricants that maycontact the product) must also beconsidered. Consideration should be

given to reagent-derived adventitiousagents.

32. The risk of contamination of startingand raw materials during their passagealong the supply chain must beassessed, with particular emphasis onTSE. Materials that come into directcontact with manufacturing equipment orthe product (such as media used inmedia fill experiments and lubricants thatmay contact the product) must also betaken into account.


35. Given that the risks of introducing contamination and the consequences to

33. Given that the risks from theintroduction of contamination and the











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the product is the same irrespective ofthe stage of manufacture, establishmentof control strategy measures to protectthe product and the preparation ofsolutions, buffers and other additionsshould be based on the principles andguidance contained in the differentsections of Annexe 1.

Where an MA or CTA provides for anallowable type and level of bioburden, forexample at active substance stage, thecontrol strategy should address themeans by which this is maintained withinthe specified limits. The controls requiredfor the quality of starting materials and onthe aseptic manufacturing process forcell-based products, where finalsterilisation is generally not possible andthe ability to remove microbial by-products is limited, assume greaterimportance.

consequences to the finished product isthe same irrespective of the stage ofmanufacture, establishment of a controlstrategy to protect the product and thepreparation of solutions, buffers andother additions should be based on theprinciples and guidance contained in theappropriate sections of Annex 1. Thecontrols required for the quality of startingand raw materials and on the asepticmanufacturing process, particularly forcell-based products, where finalsterilisation is generally not possible andthe ability to remove microbial by-products is limited, assume greaterimportance. Where an MA or CTA provides for anallowable type and level of bioburden, forexample at active substance stage, thecontrol strategy should address themeans by which this is maintained withinthe specified limits.










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26. Where sterilisation of startingmaterials is required, it should be carriedout where possible by heat. Wherenecessary, other appropriate methodsmay also be used for inactivation ofbiological materials (e.g. irradiation).

36. Where sterilization of startingmaterials is required, it should be carriedout where possible by heat. Wherenecessary, other appropriate methodsmay also be used for inactivation ofbiological materials (e.g. irradiation andfiltration).

34. Where sterilization of starting and rawmaterials is required, it should be carriedout where possible by heat. Wherenecessary, other appropriate methodsmay also be used for inactivation ofbiological materials (e.g. irradiation andfiltration).


37. Reduction in bioburden associatedwith procurement of living tissues andcells may require the use of other

measures such as antibiotics at earlymanufacturing stages. This should beavoided, but where it is necessary theiruse should be justified, they should beremoved from the manufacturing processat an early stage as possible to complywith conditions in the MA or CTA.

35. Reduction in bioburden associatedwith procurement of living tissues andcells may require the use of other

measures such as antibiotics at earlymanufacturing stages. This should beavoided, but where it is necessary theiruse should be justified, they should beremoved from the manufacturing processat the stage specified in the MA or CTA.


38. For human tissues and cells used asstarting materials for biological medicinalproducts:

36. For human tissues and cells used asstarting materials for biological medicinalproducts:


(a) Their procurement, donation andtesting in the EU is regulated underDirective 2004/23/EC and its technicaldirectives. Such EU supply sites musthold approvals from the nationalcompetent authority(ies) under this

(a) Their procurement, donation andtesting in the EU is regulated underDirective 2004/23/EC and itsimplementing Commission directives.Such EU supply sites must holdappropriate approvals from the national

Editorial changes and more details on the manufacturer.










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Directive which should be verified by themanufacturing site.

competent authority(ies) under thisDirective which should be verified as partof starting material supplier management.

(b) Where such human cells or tissuesare imported from third countries theymust meet equivalent Communitystandards of quality and safety equivalentto those laid down in Directive2004/23/EC. The traceability and seriousadverse reaction and serious adverse

event notification requirements are setout in Directive 2006/86/EC.

(b) Where such human cells or tissuesare imported from third countries theymust meet equivalent Communitystandards of quality and safety equivalentto those laid down in Directive2004/23/EC. The traceability and seriousadverse reaction and serious adverse

event notification requirements are setout in Directive 2006/86/EC.


(c) There may be some instances whereprocessing of cells and tissues used asstarting materials for biological medicinalproducts will be conducted at tissueestablishments.

All such processing steps, are under the

responsibility of the Responsible Person(RP)

(c) There may be some instances whereprocessing of cells and tissues used asstarting materials for biological medicinalproducts will be conducted at tissueestablishments, e.g. to derive early celllines or banks prior to establishing aMaster Cell Bank (MCB).Such processing steps, are under thescope of Directive 2004/23/EC, which

provides for the need of a ResponsiblePerson (RP).

Examples were incorporated and the regulatory reference is more precise.

(d) Tissue and cells are released by theRP in the tissue establishment before

(d) Tissue and cells are released by theRP in the tissue establishment before

Cross contamination is extended in this section.










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shipment to the medicinal productmanufacturer, after which normalmedicinal product starting materialcontrols apply. The test results of alltissues / cells supplied by the tissueestablishment should be available to themanufacturer of the medicinal product.Such information must be used to makeappropriate material segregation andstorage decisions.

shipment to the medicinal productmanufacturer, after which normalmedicinal product starting materialcontrols apply. The test results of alltissues / cells supplied by the tissueestablishment should be available to themanufacturer of the medicinal product.Such information must be used to makeappropriate material segregation andstorage decisions. In cases wheremanufacturing must be initiated prior toreceiving test results from the tissue

establishment, tissue and cells may beshipped to the medicinal productmanufacturer provided controls are inplace to prevent crosscontamination withtissue and cells that have been releasedby the RP in the tissue establishment.

(e) The transport of human tissues andcells to the manufacturing site is theresponsibility of the manufacturing siteswhich should have documentaryevidence of adherence to the specified

storage and transport conditions.

(e) The transport of human tissues andcells to the manufacturing site must becontrolled by a written agreementbetween the responsible parties. Themanufacturing sites should have

documentary evidence of adherence tothe specified storage and transportconditions.

The responsibilities are more detailed in the final version.










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(f) Continuation of traceabilityrequirements started at tissueestablishments through to therecipient(s), and vice versa, includingmaterials in contact with the product,should be maintained.

(f) Continuation of traceabilityrequirements started at tissueestablishments through to therecipient(s), and vice versa, includingmaterials in contact with the cells ortissues, should be maintained.


(g) A contract should be in place betweenthe manufacturer and the tissueestablishment which defines Directiveresponsibilities of each party, includingthe RP and Qualified Person.

(g) A technical agreement should be inplace between the responsible parties(e.g. manufacturers, tissueestablishment, Sponsors, MA Holder) which defines the tasks of each party,

including the RP and Qualified Person.

More detailed definitions were incorporated in this section.

39. For somatic cell therapy and t issueengineered products, the principles ofGMP shall apply after procurement ofcells and tissues.

This section of the draft version was skipped.

40. With regard to gene therapy: 37. With regard to gene therapy: No changes compared to the draft.

(a) For products consisting of viralvectors, the starting materials are thecomponents from which the viral vector is

obtained, i.e. the master virus seed or theplasmids to transfect the packaging cellsand the master cell bank of thepackaging cell line.

(a) For products consisting of viralvectors, the starting materials are thecomponents from which the viral vector is

obtained, i.e. the master virus seed or theplasmids to transfect the packaging cellsand the MCB of the packaging cell line.


(b) For products consisting of plasmids,non-viral vectors and genetically modified

(b) For products consisting of plasmids,non-viral vectors and genetically modified











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micro-organisms other than viruses orviral vectors, the starting materials arethe components used to generate theproducing cell, i.e. the plasmid, the hostbacteria and the master cell bank of therecombinant microbial cells.

micro-organisms other than viruses orviral vectors, the starting materials arethe components used to generate theproducing cell, i.e. the plasmid, the hostbacteria and the MCB of the recombinantmicrobial cells.

(c) For genetically modified cells, thestarting materials are the componentsused to obtain the genetically modifiedcells, i.e. the starting materials to

manufacture the vector and the human oranimal cell preparations.

(c) For genetically modified cells, thestarting materials are the componentsused to obtain the genetically modifiedcells, i.e. the starting materials to

manufacture the vector and the human oranimal cell preparations.


(d) The principles of GMP apply from thebank system used to manufacture thevector or plasmid used for gene transfer.

(d) The principles of GMP apply from thebank system used to manufacture thevector or plasmid used for gene transfer.


41. Where human or animal cells areused in the manufacturing process asfeeder cells, appropriate controls over thesourcing, testing, transport and storageshould be in place. If human cells are

used they should comply with Directive2004/23 EC including traceability andreporting of serious adverse events andreactions.

38. Where human or animal cells areused in the manufacturing process asfeeder cells, appropriate controls over thesourcing, testing, transport and storageshould be in place, including control of

compliance with Directive 2004/23.

This section was shortened in the final version.










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Seed lot and cell bank system Seed lot and cell bank system Seed lot and cell bank system

27. In order to prevent the unwanted driftof properties which might ensue fromrepeated subcultures or multiplegenerations, the production of biologicalmedicinal products obtained by microbialculture, cell culture or propagation inembryos and animals should be basedon a system of master and working seedlots and/or cell banks.

42. In order to prevent the unwanted driftof properties which might ensue fromrepeated subcultures or multiplegenerations, the production of biologicalmedicinal substances and productsobtained by microbial culture, cell cultureor propagation in embryos and animalsshould be based on a system of masterand working seed lots and/or cell banks.

39. In order to prevent the unwanted driftof properties which might ensue fromrepeated subcultures or multiplegenerations, the production of biologicalmedicinal substances and productsobtained by microbial culture, cell cultureor propagation in embryos and animalsshould be based on a system of masterand working virus seed lots and/or cell

banks. Such a system may not beapplicable to all types of ATMPs.

A restriction (not appropriate for ATMPs) is introduced.

28. The number of generations(doublings, passages) between the seedlot or cell bank and the finished productshould be consistent with the marketingauthorisation dossier. Scaling up of theprocess should not change thisfundamental relationship.

43. The number of generations(doublings, passages) between the seedlot or cell bank, the drug substance andfinished product should be consistentwith specifications in the MA or CTA.

40. The number of generations(doublings, passages) between the seedlot or cell bank, the active biologicalsubstance and the finished productshould be consistent with specificationsin the MA or CTA.


29. Seed lots and cell banks should beadequately characterised and tested forcontaminants. Their suitability for useshould be further demonstrated by theconsistency of the characteristics andquality of the successive batches of

44. As part of product lifecyclemanagement, establishment of seed lotsand cell banks, including master andworking generations, should beperformed under circumstances whichare demonstrably appropriate. This

41. As part of product lifecyclemanagement, establishment of seed lotsand cell banks, including master andworking generations, should beperformed under circumstances whichare demonstrably appropriate. This











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product. Seed lots and cell banks shouldbe established, stored and used in such away as to minimise the risks ofcontamination or alteration.

should include an appropriately controlledenvironment to protect the seed lot andthe cell bank and the personnel handlingit. During the establishment of the seedlot and cell bank, no other living orinfectious material (e.g. virus, cell lines orcell strains) should be handledsimultaneously in the same area or bythe same persons. For stages prior to themaster seed generation, where only theprinciples of GMP may be applied,documentation in line with ICH Q5D

should be available to support traceabilityincluding issues related to componentsused during development with potentialimpact on product safety (e.g. reagents ofbiological origin) from initial sourcing andgenetic development if applicable. Forvaccines the requirements of Ph Eurmonograph 2005;153 “Vaccines forhuman use” will apply.

should include an appropriately controlledenvironment to protect the seed lot andthe cell bank and the personnel handlingit. During the establishment of the seedlot and cell should be handledsimultaneously in the same area or bythe same persons.

For stages prior to the master seed orcell bank generation, where only theprinciples of GMP may be applied,documentation should be available to

support traceability including issuesrelated to components used duringdevelopment with potential impact onproduct safety (e.g. reagents of biologicalorigin) from initial sourcing and geneticdevelopment if applicable. For vaccinesthe requirements of Ph Eur monograph2005;153 “Vaccines for human use” willapply.

30. Establishment of the seed lot and cellbank should be performed in a suitablycontrolled environment to protect the

seed lot and the cell bank and, ifapplicable, the personnel handling it.During the establishment of the seed lotand cell bank, no other living or infectiousmaterial (e.g. virus, cell lines or cellstrains) should be handled

45. Following the establishment of masterand working cell banks and seed lots,quarantine and release procedures

should be followed.

This should include adequatecharacterization and testing forcontaminants. Their on-going suitabilityfor use should be further demonstrated

42. Following the establishment of masterand working cell banks and master andworking seed lots, quarantine and

release procedures should be followed.This should include adequatecharacterization and testing forcontaminants. Their on-going suitabilityfor use should be further demonstratedby the consistency of the characteristics











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simultaneously in the same area or bythe same persons.

by the consistency of the characteristicsand quality of the successive batches ofproduct. Evidence of the stability andrecovery of the seeds and banks shouldbe documented and records should bekept in a manner permitting trendevaluation.

and quality of the successive batches ofproduct. Evidence of the stability andrecovery of the seeds and banks shouldbe documented and records should bekept in a manner permitting trendevaluation.

31. Evidence of the stability and recoveryof the seeds and banks should bedocumented. Storage containers should

be hermetically sealed, clearly labelledand kept at an appropriate temperature.An inventory should be meticulously kept.Storage temperature should be recordedcontinuously for freezers and properlymonitored for liquid nitrogen. Anydeviation from set limits and anycorrective action taken should berecorded.

46. Seed lots and cell banks should bestored and used in such a way as tominimize the risks of contamination, (e.g.

stored in the vapour phase of liquidnitrogen in sealed containers) oralteration. Control measures for thestorage of different seeds and/or cells inthe same area or equipment shouldprevent mix-up and take account theinfectious nature of the materials toprevent cross contamination.

43. Seed lots and cell banks should bestored and used in such a way as tominimize the risks of contamination, (e.g.

stored in the vapour phase of liquidnitrogen in sealed containers) oralteration. Control measures for thestorage of different seeds and/or cells inthe same area or equipment shouldprevent mix-up and take account theinfectious nature of the materials toprevent cross contamination.


32. Only authorised personnel should beallowed to handle the material and this

handling should be done under thesupervision of a responsible person.Access to stored material should becontrolled. Different seed lots or cellbanks should be stored in such a way toavoid confusion or cross-contamination. It

44. Cell based medicinal products areoften generated from a cell stock

obtained from limited number ofpassages. In contrast with the two tieredsystem of Master and Working cellbanks, the number of production runsfrom a cell stock is limited by the numberof aliquots obtained after expansion and

This section is newly introduced.










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is desirable to split the seed lots and cellbanks and to store the parts at differentlocations so as to minimise the risks oftotal loss.

does not cover the entire life cycle of theproduct. Cell stock changes should becovered by a validation protocol.

33. All containers of master or workingcell banks and seed lots should betreated identically during storage. Onceremoved from storage, the containersshould not be returned to the stock.

47. Storage containers should be sealed,clearly labelled and kept at anappropriate temperature. A stockinventory must be kept. The storagetemperature should be recordedcontinuously and, where used, the liquid

nitrogen level monitored. Deviation fromset limits and corrective and preventiveaction taken should be recorded.

45. Storage containers should be sealed,clearly labelled and kept at anappropriate temperature. A stockinventory must be kept. The storagetemperature should be recordedcontinuously and, where used, the liquid

nitrogen level monitored. Deviation fromset limits and corrective and preventiveaction taken should be recorded.


48. It is desirable to split stocks and tostore the split stocks at different locationsso as to minimize the risks of total loss.The controls at such locations shouldprovide the assurances outlined in thepreceding paragraphs.

46. It is desirable to split stocks and tostore the split stocks at different locationsso as to minimize the risks of total loss.The controls at such locations shouldprovide the assurances outlined in thepreceding paragraphs.


49. The storage and handling conditions

for stocks should be managed accordingto the same procedures and parameters.Once containers are removed from theseed lot / cell bank management system,the containers should not be returned tostock.

47. The storage and handling conditions

for stocks should be managed accordingto the same procedures and parameters.Once containers are removed from theseed lot / cell bank management system,the containers should not be returned tostock.

No changes compared to the

draft.










Original 2004


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Operating principles Operating principles Operating principles

50. Change management should, on aperiodic basis, consider the effects,including cumulative effects of changes(e.g. in the process) on the quality, safetyand efficacy of the product.

48. Change management should, on aperiodic basis, take into account theeffects, including cumulative effects ofchanges (e.g. to the process) on thequality, safety and efficacy of the finishedproduct.


51. Critical operational (process)parameters, or other input parameters

which affect product quality, need to beidentified, validated, documented and beshown to be maintained withinrequirements.

49. Critical operational (process)parameters, or other input parameters

which affect product quality, need to beidentified, validated, documented and beshown to be maintained withinrequirements.


52.

Heat stable articles and materialsentering a clean area or clean/containedarea should do so through a double-ended autoclave or oven.

Heat labile articles and materials shouldenter through an air lock with interlockeddoors where they are subject to effectivesurface sanitisation procedures.Sterilisation of articles and materialselsewhere is acceptable provided that

50. A control strategy for the entry ofarticles and materials into productionareas should be based on QRMprinciples. For aseptic processes, heatstable articles and materials entering aclean area or clean/contained areashould preferably do so through adouble-ended autoclave or oven.

Heat labile articles and materials shouldenter through an air lock with interlockeddoors where they are subject to effectivesurface sanitisation procedures.Sterilisation of articles and materialselsewhere is acceptable provided that

Additional reference to quality risk management and supplementing “multi wrapping”.










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they are double wrapped and enterthrough an airlock with the appropriatesurface sanitisation precautions.

they are multiple wrappings, asappropriate to the number of stages ofentry to the clean area, and enter throughan airlock with the appropriate surfacesanitization precautions.

34. The growth promoting properties ofculture media should be demonstrated.37. If possible, media should be sterilisedin situ. In-line sterilising filters for routineaddition of gases, media, acids or alkalis,defoaming agents etc. to fermenters

should be used where possible.

53. The growth promoting properties ofculture media should be demonstrated tobe suitable for its intended use. Ifpossible, media should be sterilized insitu. In-line sterilizing filters for routineaddition of gases, media, acids or alkalis,

anti-foaming agents etc. to fermentersshould be used where possible.

51. The growth promoting properties ofculture media should be demonstrated tobe suitable for its intended use. Ifpossible, media should be sterilized insitu. In-line sterilizing filters for routineaddition of gases, media, acids or alkalis,

anti-foaming agents etc. to fermentersshould be used where possible.


35. Addition of materials or cultures tofermenters and other vessels and thetaking of samples should be carried outunder carefully controlled conditions toensure that absence of contamination ismaintained. Care should be taken toensure that vessels are correctlyconnected when addition or samplingtake place.

54. Addition of materials or cultures tofermenters and other vessels andsampling should be carried out undercarefully controlled conditions to preventcontamination. Care should be taken toensure that vessels are correctlyconnected when addition or samplingtakes place.

52. Addition of materials or cultures tofermenters and other vessels andsampling should be carried out undercarefully controlled conditions to preventcontamination. Care should be taken toensure that vessels are correctlyconnected when addition or samplingtakes place.


Continuous monitoring of someproduction processes (e.g. fermentation)may be necessary, such data shouldform part of the batch record. Wherecontinuous culture is used, specialconsideration should be given to the

53. Continuous monitoring of someproduction processes (e.g. fermentation)may be necessary, such data shouldform part of the batch record. Wherecontinuous culture is used, specialconsideration should be given to the

No changes compared to the draft, the section got a new number










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quality control requirements arising fromthis type of production method.

quality control requirements arising fromthis type of production method.

36. Centrifugation and blending ofproducts can lead to aerosol formation,and containment of such activities toprevent transfer of live micro-organismsis necessary.

55. Centrifugation and blending ofproducts can lead to aerosol formationand containment of such activities toprevent transfer of live microorganisms isnecessary.

54. Centrifugation and blending ofproducts can lead to aerosol formationand containment of such activities tominimise cross-contamination isnecessary.


56. Accidental spillages, especially of live

organisms, must be dealt with quicklyand safely. Validated decontaminationmeasures should be available for eachorganism or groups of related organisms.Where different strains of single bacteriaspecies or very similar viruses areinvolved, the decontamination processmay be validated with one representativestrain, unless there is reason to believethat they may vary significantly in theirresistance to the agent(s) involved.

55. Accidental spillages, especially of live

organisms, must be dealt with quicklyand safely. Qualified decontaminationmeasures should be available for eachorganism or groups of related organisms.Where different strains of single bacteriaspecies or very similar viruses areinvolved, the decontamination processmay be validated with one representativestrain, unless there is reason to believethat they may vary significantly in theirresistance to the agent(s) involved.


57. If obviously contaminated, such as by

spills or aerosols, or if a potentiallyhazardous organism is involved,production and control materials,including paperwork, must be adequatelydisinfected, or the information transferredout by other means.

56. If obviously contaminated, such as by

spills or aerosols, or if a potentiallyhazardous organism is involved,production and control materials,including paperwork, must be adequatelydisinfected, or the information transferredout by other means.

No changes compared to the

draft.










Original 2004


Draft 2010


Final January 2013


38. Careful consideration should be givento the validation of any necessary virusremoval or inactivation undertaken (seeCPMP notes for guidance).

58. Careful consideration should be givento the validation of any methods forsterilisation, disinfection, virus removal orinactivation undertaken (see CHMPguidance).


39. In cases where a virus inactivation orremoval process is performed duringmanufacture, measures should be takento avoid the risk of recontamination oftreated products by nontreated products.

59. In cases where a virus inactivation orremoval process is performed duringmanufacture, measures should be takento avoid the risk of recontamination oftreated products by non-treated products.

57. In cases where a virus inactivation orremoval process is performed duringmanufacture, measures should be takento avoid the risk of recontamination oftreated products by non-treated products.


60. For products that are inactivated bythe addition of a reagent, the processshould ensure the complete inactivationof live organism. In addition to thethorough mixing of culture and inactivant,consideration should be given to contactof all product-contact surfaces exposedto live culture and the transfer to asecond vessel.

58. For products that are inactivated bythe addition of a reagent (e.g. micro-organisms in the course of vaccinemanufacture) the process should ensurethe complete inactivation of liveorganism. In addition to the thoroughmixing of culture and inactivant,consideration should be given to contactof all product-contact surfaces exposedto live culture and, where required, thetransfer to a second vessel.


40. A wide variety of equipment is used

for chromatography, and in general suchequipment should be dedicated to thepurification of one product and should besterilised or sanitised between batches.The use of the same equipment atdifferent stages of processing should be


for chromatography. Quality riskmanagement principles should be usedto devise the controls on matrices, thehousings and associated equipment.Consideration should be given to theneed to dedicate chromatography


for chromatography. QRM principlesshould be used to devise the controlstrategy on matrices, the housings andassociated equipment when used incampaign manufacture and in multi-product environments.

The requirements were

reduced in this section.










Original 2004


Draft 2010


Final January 2013


discouraged. Acceptance criteria, lifespan and sanitation or sterilisationmethod of columns should be defined.

equipment to the purification of oneproduct in multi-product environments and the need for equipment to besterilized or sanitized between batches.The use of the same matrix at differentstages of processing is discouraged.Acceptance criteria, operating conditions,regeneration methods, life span andsanitization or sterilization methods ofcolumns should be defined.

The re-use of the same matrix at differentstages of processing is discouraged.Acceptance criteria, operating conditions,regeneration methods, life span andsanitization or sterilization methods ofcolumns should be defined.

62. Where irradiated equipment andmaterials are used, Annex 12 should beconsulted for further guidance.

60. Where irradiated equipment andmaterials are used, Annex 12 toEudraLex, Volume 4, should beconsulted for further guidance.


63. There should be a system to assurethe integrity and closure of containersafter filling where the final products orintermediates represent a special riskand procedures to deal with any leaks orspillages. Filling and packagingoperations need to have procedures inplace to maintain the product within any

specified limits, e.g. time and/ortemperature.

61. There should be a system to assurethe integrity and closure of containersafter filling where the final products orintermediates represent a special riskand procedures to deal with any leaks orspillages. Filling and packagingoperations need to have procedures inplace to maintain the product within any

specified limits, e.g. time and/ortemperature.


64. Activities in handling vials containinglive biological agents must be performedin such a way to prevent the

62. Activities in handling vials containinglive biological agents must be performedin such a way to prevent the

Editorial changes concerning risk analysis and management.










Original 2004


Draft 2010


Final January 2013


contamination of other products or egressof the live agents into the workenvironment or the external environment.This risk assessment should take intoconsideration the viability of suchorganisms and their biologicalclassification.

contamination of other products or egressof the live agents into the workenvironment or the external environment.The viability of such organisms and theirbiological classification should take intoconsideration as part of the managementof such risks.

65. During finishing operations, such asformulation, filling and packaging,additional measures, dependent on thespecific needs of the biological product,

may be required. These may include thesequence of additions, mixing speeds,time and temperature controls, limits onexposure to light and cleaningprocedures in the event of spillages.


66. Care should be taken in thepreparation, printing, storage andapplication of labels, including anyspecific text for patient-specific productsor signifying genetic modification of thecontents on the primary container andsecondary packaging. In the case of

products used for autologous use, theunique patient identifier and thestatement “for autologous use only”should be indicated on the immediatelabel.

63. Care should be taken in thepreparation, printing, storage andapplication of labels, including anyspecific text for patient-specific productsor signifying the use of geneticengineering of the contents on theimmediate and outer packaging. In the

case of ATMPs used for autologous use,the unique patient identifier and thestatement “for autologous use only”should be indicated on the outerpackaging or, where there is no outerpackaging, on the immediate packaging.

Only editorial changes.










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Final January 2013


67. The compatibility of labels with ultra-low storage temperatures, where suchtemperatures are used, should beverified.

64. The compatibility of labels with ultra-low storage temperatures, where suchtemperatures are used, should beverified.


68. Where donor and /or animal healthinformation becomes available afterprocurement, which affects productquality, it should be taken into account inrecall procedures.

65. Where donor (human or animal) health information becomes availableafter procurement, which affects productquality, it should be taken into account inrecall procedures.


Quality control Quality control Quality control

41. In-process controls play a speciallyimportant role in ensuring the consistencyof the quality of biological medicinalproducts. Those controls which arecrucial for quality (e.g. virus removal) butwhich cannot be carried out on thefinished product, should be performed atan appropriate stage of production.

69. In-process controls have a greaterimportance in ensuring the consistency ofthe quality of biological medicinalproducts than for conventional products.In-process control testing should beperformed at appropriate stages ofproduction to control those conditionsthat are important for the quality of thefinished product (e.g., virus removal,residual DNA content).

66. In-process controls have a greaterimportance in ensuring the consistency ofthe quality of biological active substanceand medicinal products than forconventional products. In-process controltesting should be performed atappropriate stages of production tocontrol those conditions that areimportant for the quality of the finishedproduct.


42. It may be necessary to retainsamples of intermediate products insufficient quantities and underappropriate storage conditions to allowthe repetition or confirmation of a batchcontrol.

70. Where in-process hold steps exist,consideration should be given to theinclusion of final product batches madefrom materials held for their maximum in-process periods in the on-going stabilityprogramme.

67. Where intermediates can be storedfor extended periods of time (days,weeks or longer), consideration shouldbe given to the inclusion of finishedproduct batches made from materialsheld for their maximum in-processperiods in the on-going stabilityprogramme.

More details on requirements were incorporated.










Original 2004


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Final January 2013


43. Continuous monitoring of certainproduction processes is necessary, forexample fermentation. Such data shouldform part of the batch record.

71. Certain types of cells (e.g. autologouscells used in ATMPs) may be available inlimited quantities and, where allowed inthe MA, a modified testing and sampleretention strategy may be developed anddocumented.

68. Certain types of cells (e.g. autologouscells used in ATMPs) may be available inlimited quantities and, where allowed inthe MA, a modified testing and sampleretention strategy may be developed anddocumented.


44. Where continuous culture is used,special consideration should be given tothe quality control requirements arisingfrom this type of production method.

69. For cell-based ATMPs, sterility testsshould be conducted on antibiotic-freecultures of cells or cell banks to provideevidence for absence of bacterial andfungal contamination and to be able to

detection fastidious organisms whereappropriate.

This section was newly incorporated.

72. For products with a short shelf life,and which need batch certification beforecompletion of all end product qualitycontrol tests (e.g. sterility tests) a suitablecontrol strategy must be in place.

Such controls need to be built onenhanced understanding of product and

process performance and take intoaccount the controls and attributes ofinput materials.There should be a description of theentire release procedure, including theresponsibilities of the different personnel

70. For biological medicinal products witha short shelf life, which for the purposesof the annex is taken to mean a period of14 days or less, and which need batchcertification before completion of all endproduct quality control tests (e.g. sterilitytests) a suitable control strategy must bein place.Such controls need to be built onenhanced understanding of product and

process performance and take intoaccount the controls and attributes ofstarting and raw materials.The exact and detailed description of theentire release procedure, including theresponsibilities of the different personnel

Editorial amendments and some specifications










Original 2004


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Final January 2013


involved in assessment of production andanalytical data.

A continuous assessment of theeffectiveness of the quality assurancesystem must be in place.

Where end product tests are not possibledue to short shelf lives, alternativemethods of obtaining equivalent data topermit batch certification should beconsidered (e.g. rapid microbiological

methods). The procedure for batchcertification and release may be carriedout in two or more stages - before andafter full end process analytical testresults are available:

involved in assessment of production andanalytical data is essential.A continuous assessment of theeffectiveness of the quality assurancesystem must be in place includingrecords kept in a manner which permittrend evaluation. Where end producttests are not available due to their shortshelf life, alternative methods of obtainingequivalent data to permit initial batchcertification should be considered (e.g.rapid microbiological methods). The

procedure for batch certification andrelease may be carried out in two or morestages - :

a) Assessment by designated person(s)of batch processing records and resultsfrom environmental monitoring (whereavailable) which should cover productionconditions, all deviations from normalprocedures and the available analytical

results for review and conditionalcertification by the Qualified Person.

a) Assessment by designated person(s)of batch processing records, results fromenvironmental monitoring (whereavailable) which should cover productionconditions, all deviations from normalprocedures and the available analytical

results for review in preparation for theinitial certification by the QualifiedPerson.











Original 2004


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Final January 2013


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b) Assessment of the final analytical testsand other information available beforeend product dispatch for final productcertification by the Qualified Person.

b) Assessment of the final analytical testsand other information available for finalcertification by the Qualified Person.


c) Records should be kept in a mannerwhich permits trend evaluation.


d) A procedure should be in place todescribe the measures to be taken(including liaison with clinical staff) whereout of specification test results are

obtained after product dispatch. Suchevents should be fully investigated andthe relevant corrective and preventativeactions taken to prevent recurrencedocumented.

A procedure should be in place todescribe the measures to be taken(including liaison with clinical staff) whereout of specification test results are

obtained. Such events should be fullyinvestigated and the relevant correctiveand preventive actions taken to preventrecurrence documented.


Part B. SPECIFIC GUIDANCE ONSELECTED PRODUCT TYPES

Part B. SPECIFIC GUIDANCE ONSELECTED PRODUCT TYPES

Part B is very detailed for specific product types.Therefore, the comparison of this part is not included in the synopsis.

...




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Comparison of Different Versions of Annex 2 EU Guide to GMP

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