{"id":380,"date":"2016-08-15T10:51:35","date_gmt":"2016-08-15T00:51:35","guid":{"rendered":"http:\/\/paulyeatman.net.au\/?p=380"},"modified":"2020-07-29T14:37:49","modified_gmt":"2020-07-29T03:37:49","slug":"notes-on-international-standard-iso-13408-1-2008","status":"publish","type":"post","link":"https:\/\/paulyeatman.net.au\/index.php\/2016\/08\/15\/notes-on-international-standard-iso-13408-1-2008\/","title":{"rendered":"Notes on International Standard ISO 13408-1: 2008"},"content":{"rendered":"<p>One of the main International Standards used as a reference document in a sterile pharmaceutical microbiology laboratory is ISO13408 &#8211; Aseptic Processing of Health Care Products .\u00a0 <a href=\"http:\/\/paulyeatman.net.au\/index.php\/2012\/11\/06\/notes-on-international-standard-iso-13408-1-1998e\/\" target=\"_blank\" rel=\"noopener\">Long ago, I reviewed the 1998 edition<\/a>.\u00a0 More recently, I acquired ISO 13208-1 (2008), so I compared my notes from the 1988 version with what is stated in the 2008 version.\u00a0 The use of <em>italics<\/em> is my way of emphasising points.\u00a0 <span style=\"color: #0000ff;\">Notes on changes are in blue<\/span>.<\/p>\n<p><span style=\"color: #0000ff;\"><strong>INTRODUCTION<\/strong><\/span><\/p>\n<p><span style=\"color: #0000ff;\">When I reviewed the 1998 edition, I did not note down any of the introduction.<\/span><\/p>\n<ul>\n<li><span style=\"color: #0000ff;\">Anything labelled as sterile needs to made under tight control as part of a Quality Management System<\/span><\/li>\n<li><span style=\"color: #0000ff;\">This part of the ISO focusses on the risks to the maintenance of sterility<\/span><\/li>\n<li><span style=\"color: #0000ff;\">All possible sources of contamination need to be controlled and a risk based approach is recommended<\/span><\/li>\n<li><span style=\"color: #0000ff;\">Appropriate validation of the aseptic process is needed and process simulation trials are an essential part of this<\/span><\/li>\n<\/ul>\n<p><!--more--><\/p>\n<p><span style=\"color: #0000ff;\"><strong>PART 1: GENERAL REQUIREMENTS<\/strong><\/span><\/p>\n<p><span style=\"color: #0000ff;\"><strong>1. Scope<\/strong><\/span><\/p>\n<p><span style=\"color: #0000ff;\">The ISO specifies the general requirements and offers guidance on the processes, programs, procedures, validation and control of the manufacturing process for sterile manufacture<\/span><\/p>\n<p><strong>3. Terms and definitions<\/strong><\/p>\n<p><span style=\"color: #0000ff;\">Terms and definitions have moved to Section 3.<\/span><\/p>\n<p><strong>APA<\/strong> = Aseptic Processing Area<\/p>\n<ul>\n<li>\u2018<strong>bioburden<\/strong>\u2019 <span style=\"color: #0000ff;\">now defined as: population of viable microorganisms on or<del><\/del> in a health care product and\/or sterile barrier system<\/span><\/li>\n<li>\u2018<strong>disinfectant<\/strong>\u2019 <span style=\"color: #0000ff;\">now defined as: chemical agent that is able to reduce the number of viable microorganisms <\/span><span style=\"color: #0000ff;\"><br \/>\n<\/span><\/li>\n<li>\u2018<strong>media fill<\/strong>\u2019 is defined as: method of evaluating an aseptic process using a microbial growth medium\u2026media fills are understood to be synonymous to process simulation tests, simulated product fills, simulated filling operations, broth trials, broth fills, etc.\u201d <span style=\"color: #0000ff;\">no longer defined<\/span><\/li>\n<li>\u2018<strong>product sterilising filter<\/strong>\u2019 is defined as: porous material with a nominal rating of less than or equal to 0.22mm, capable of retaining a defined number of microorganisms using defined challenge test and conditions. <span style=\"color: #0000ff;\">no longer defined<\/span><\/li>\n<li>\u2018<strong>sterile<\/strong>\u2019 is defined as \u201cstate of being free from viable microorganisms. NOTE: in practice, no such absolute statement regarding the absence of microorganisms can be proven\u201d<\/li>\n<li><strong>\u2018sterilisation\u2019<\/strong> is defined as \u201cvalidated process used to render a product free from viable microorganisms. NOTE: The number of microorganisms that survive a sterilisation process can be expressed in terms of probability. While the probability may be reduced to a very low number, it can never be reduced to zero.\u201d<\/li>\n<\/ul>\n<p><strong>SECTION 3: QUALITY MANAGEMENT SYSTEMS\u00a0 <\/strong><span style=\"color: #0000ff;\">Now 4. Quality System Elements<\/span><strong><br \/>\n<\/strong><\/p>\n<ul>\n<li>The Quality Management system is governed by the requirements in ISO 9001 and\/or <span style=\"color: #0000ff;\">ISO 13485 Medical Devices &#8211; Quality Management Systems<\/span> <em>unless<\/em> a superseding national, regional or international GMP is employed.<\/li>\n<\/ul>\n<p><strong>SECTION 5: FACILITY DESIGN\u00a0 <\/strong><span style=\"color: #0000ff;\">Now 6. Manufacturing Environment<\/span><strong><br \/>\n<\/strong><\/p>\n<p><span style=\"color: #0000ff;\"><em>6.1 General<\/em><\/span><\/p>\n<p><span style=\"color: #0000ff;\"><em>6.1.1\u00a0 Manufacutring environment should be designed and built in accordance with ISO 14644-4 (2001) Cleanrooms and associated controlled environments \u2014 Part 4: Design, construction and start-up<\/em><\/span><\/p>\n<p><strong>SECTION 12 MATERIALS AND EQUIPMENT DELIVERED TO ASEPTIC AREAS <\/strong><span style=\"color: #0000ff;\">Now 6.4.2 Introduction of materials and components into the APA<\/span><strong><br \/>\n<\/strong><\/p>\n<p>Section 12.3 Bioburden<\/p>\n<p>\u201cThe characterisation and resistance to inactivation of the bioburden on components and equipment that are introduced into the APA shall be periodically determined\u201d.<\/p>\n<p><span style=\"color: #0000ff;\">Lots of reshuffling of information about in this section.\u00a0 Either expands on the <a style=\"color: #0000ff;\" href=\"http:\/\/paulyeatman.net.au\/index.php\/2016\/08\/11\/notes-on-pics-guide-for-good-manufacturing-practice-for-medicinal-products-2009\/\" target=\"_blank\" rel=\"noopener\">PIC\/S recommendations<\/a>, of they summarize this section.\u00a0 Lots of great design information in this section. Just what one would expect.\u00a0 From a VEM standpoint, pay particular attention to <strong>6.6 Cleanroom qualification<\/strong> and<strong> 6.8 Environmental and personnel monitoring programs<\/strong>.\u00a0 Loads of juicy information.<\/span><\/p>\n<p><strong>SECTION 7: SUPPORT AREAS OUTSIDE THE APA &#8211;<\/strong><span style=\"color: #0000ff;\"> Removed.\u00a0 Seems to be incorporated into Section 6.8 Environmental and personnel monitoring programmes<strong><br \/>\n<\/strong><\/span><\/p>\n<ul>\n<li><del>Section 7.1<\/del> <span style=\"color: #0000ff;\">6.8.1.6<\/span> <del>The disinfection and environmental monitoring of this area (Class 100 000) may be less frequent than that utilised for the processing zones.<\/del> <span style=\"color: #0000ff;\">Direct and indirect support zones may be monitored less frequently than the critical processing zone&#8230;<\/span><\/li>\n<li><del>Section 7.2<\/del> <span style=\"color: #0000ff;\">6.8.1.4\u00a0<\/span> \u201cSupport areas shall be monitored routinely for the presence of microorganisms, i.e. environmental flora\/isolates\u201d <span style=\"color: #0000ff;\">The frequency of monitoring for the different zones shall be specified.<\/span><\/li>\n<\/ul>\n<p><strong>SECTION 14 ENVIRONMENTAL MONITORING PROGRAMMES <\/strong><span style=\"color: #0000ff;\">Now 6.8 Environmental and personnel monitoring programmes<\/span><strong><br \/>\n<\/strong><\/p>\n<p>Section 14.2 Sampling<\/p>\n<p>Section 14.2.1 Processing zones and frequency of sampling<\/p>\n<ul>\n<li><del>Section 14.2.1.1 page 14: \u201cProduct contact and material contact sites\u2026monitored during and\/or immediately after completion of the filling operation.\u201d<\/del> <span style=\"color: #0000ff;\">6.8.1.5\u00a0 The critical processing zone shall be monitored during each operational shift.\u00a0 Monitoring approaches shall not compromise the sterility of a product.\u00a0 NOTE Surface sampling is typically done at the end of the operation.<\/span><\/li>\n<li><del>Section 14.2.1.3<\/del> <span style=\"color: #0000ff;\">6.8.1.6<\/span>\u00a0<del> \u201cOther processing zones\u2026monitored at a defined frequency based on classification of the zones and testing data.\u201d<\/del>\u00a0 <span style=\"color: #0000ff;\">Direct and indirect support zones may be monitored less frequently&#8230;<\/span><\/li>\n<li><del>Section 14.2.1.5 page 14:<\/del> 6.8.1.4 (b)\u00a0 \u201c<del>The frequency of such monitoring for different facilities shall be based on historical environmental monitoring data and the type of product and process.\u201d<\/del> <span style=\"color: #0000ff;\">&#8230;the frequency shall be based on historical environmental monitoring data and with consideration of regulatory requirements.<\/span><\/li>\n<\/ul>\n<p><del>Section 14.2.2 Sampling sites<\/del><\/p>\n<p><span style=\"color: #0000ff;\">6.8.3.2 Sampling sites shall be selected based on a contamination risk assessment specific to a particular aseptic processing operation<\/span>. Sampling sites should be derived from and <em>consistent with those used during validation<\/em> activities<\/p>\n<p><strong>SECTION 14.3 MICROBIOLOGICAL ENVIRONMENTAL MONITORING PROGRAMME <\/strong><span style=\"color: #0000ff;\">Now incorporated into 6.8 Environmental and personnel; monitoring programmes<\/span><strong><strong><strong><br \/>\n<\/strong><\/strong><\/strong>Section 14.3.1 General<\/p>\n<ul>\n<li>Section 14.3.1.1 page 14: \u201cPeriodic monitoring shall include methods for yeast, moulds and other microorganisms.\u201d<\/li>\n<li>Section 14.3.1.2 page 14: \u201cValidated recovery methods and calibrated equipment shall be used.\u201d<\/li>\n<li>Section 14.3.1.4 page 14: \u201cAdditional microbial and particulate monitoring shall be performed following start-up of operations or following periods of extended shut-down or modifications to the facility.\u201d<\/li>\n<li><span style=\"color: #0000ff;\">The above is now nicely summarised in section 6.8.5 Monitoring procedures<\/span><\/li>\n<\/ul>\n<p>Section 14.3.3 Microbiological sampling techniques<\/p>\n<p><del>\u201cAir sampling, using a volumetric sampling method, and other sampling methods, e.g. settle plates, swabs and contact plates, shall be used as appropriate to evaluate the microbiological quality of zones within the APA.\u201d<\/del>\u00a0 <span style=\"color: #0000ff;\">Specifics are now in 6.8.3 Sampling for microbiological environmental monitoring<\/span><\/p>\n<p><strong>SECTION 15 ALERT AND ACTION LEVELS <\/strong><span style=\"color: #0000ff;\">Now incorporated into 6.8 Environmental and personnel; monitoring programmes<\/span><strong><strong><br \/>\n<\/strong><\/strong>Section 15.1 Development of alert and action levels\u00a0<span style=\"color: #0000ff;\"> Now in 6.8.1.1 Alert and action levels and are derived from and consistent with results obtained from data trend analysis <em>though the regs state what your limits should be<\/em><\/span><\/p>\n<ul>\n<li><del>Page 15 \u201cNOTE1 Alert and action levels\u2026derived from\u2026results obtained during the aseptic process validation. Historical data\u2026may also be appropriate..\u201d<\/del><\/li>\n<li><del>Page 15 \u201cNOTE 2 Often one level is appropriate\u2026for critical processing zones.\u201d<\/del><\/li>\n<li><del>Page 15 \u201cNOTE 3 Adjustments of\u2026levels could be appropriate, based (on)\u2026media fill re-evaluations and\u2026monitoring data.\u201d<\/del><\/li>\n<\/ul>\n<p><del>Section 15.2<\/del> <span style=\"color: #0000ff;\">6.8.6.2<\/span> Review of Data <span style=\"color: #0000ff;\">and trend analysis<\/span><\/p>\n<p><span style=\"color: #0000ff;\">Results need to be reviewed against established alert and action levels.\u00a0 Impact of excursions needs to be assessed.<\/span><\/p>\n<ul>\n<li><del>\u201c\u2026Results of all environmental monitoring\u2026reviewed in a timely manner against the alert and action levels\u2026\u201d<\/del><\/li>\n<\/ul>\n<p><del>Section 15.3 Environmental monitoring trend analysis<\/del><\/p>\n<ul>\n<li><del>Section 15.3.1<\/del> <span style=\"color: #0000ff;\">6.8.6.2.2<\/span> \u201cEnvironmental data shall be analysed for trends on a routine basis.\u201d<\/li>\n<li><del>Section 15.3.2<\/del> <span style=\"color: #0000ff;\">6.8.6.3.1<\/span> \u201cAn investigation shall be initiated when necessary as indicated by trend data.\u201d\u00a0 <span style=\"color: #0000ff;\">Investigations carried out using documented procedures shall be initiated following <span style=\"text-decoration: underline;\"><strong>events that indicate a possible loss<\/strong><\/span> of environmental control such as &lt;details provided&gt;<\/span><\/li>\n<li><\/li>\n<li>\n<div><\/div>\n<p><strong>SECTION 16 INVESTIGATIONS AND REPORTS <\/strong><span style=\"color: #0000ff;\">Now incorporated into 6.8 Environmental and personnel monitoring programmes<\/span><strong><strong><strong><br \/>\n<\/strong><\/strong><\/strong><\/li>\n<\/ul>\n<ul>\n<li><del>Section 16.1.1 page 15: \u201cInvestigations shall be conducted for unusual circumstances, extended mechanical breakdowns, or when action levels are exceeded.\u201d<\/del><\/li>\n<li><del>Section 16.1.2 page 15: \u201cWritten investigation procedures shall be available and\u2026include\u2026data to be collected, extent of the problem, impact on product or environmental control, quarantine of the product, whether the environmental control has been attained, follow-up testing and notification of affected responsible personnel.\u201d<\/del>\u00a0 <span style=\"color: #0000ff;\">Similar text is now in 6.8.6.3.1<\/span><del><br \/>\n<\/del><\/li>\n<\/ul>\n<p><del>Section 16.2 Investigation testing<\/del><\/p>\n<ul>\n<li><del>\u201cInvestigation testing shall be designed to locate the source of the problem and demonstrate that the area, process or equipment is once again under control. Revalidation may be necessary based on the outcome of the investigation.\u201d\u00a0<\/del><span style=\"color: #0000ff;\"> Statement removed.\u00a0 Closest is 10.6.1.3 which says requalification should be performed where investigation identifies the need<\/span><\/li>\n<\/ul>\n<p><del>Section 16.3 Investigation report<\/del><\/p>\n<ul>\n<li><del>Section 16.3.1<\/del> <span style=\"color: #0000ff;\">6.8.6.3.2 \u201c<\/span>The investigation shall be documented\u2026\u201d<\/li>\n<li><del>Section 16.3.2 page 16: \u201cThe report shall be written and approved by management..\u201d\u00a0<\/del><span style=\"color: #0000ff;\"> Statement to this effect in 6.8.6.3.2<\/span><\/li>\n<\/ul>\n<p><strong>SECTION 21.11 MICROBIOLOGICAL AND PARTICULATE ENVIRONMENTAL MONITORING\u00a0 <\/strong><span style=\"color: #0000ff;\">Incorporated into\u00a0 Section 6.8 Environmental and personnel monitoring programs <\/span><strong><br \/>\n<\/strong><\/p>\n<ul>\n<li>\u201cA programme for microbiological monitoring of product transfer and freeze-drying shall be implemented.\u201d <span style=\"color: #0000ff;\">Other contamination risks not specifically associated with aseptic processing are not addressed in this part of ISO 13408<\/span><\/li>\n<\/ul>\n<p><strong>SECTION 4: PERSONNEL <\/strong><span style=\"color: #0000ff;\">Now 8. Personnel<br \/>\n<\/span><\/p>\n<ul>\n<li><del>Section 4.1.2 Page 5:<\/del> <span style=\"color: #0000ff;\">8.1.2<\/span> The effectiveness of the <del>defined<\/del> <span style=\"color: #0000ff;\">documented<\/span> procedures shall be evaluated at\u00a0 <span style=\"color: #0000ff;\">intervals defined by the manufacturer<\/span> <del>defined intervals (with respect to personnel training).<\/del><\/li>\n<li><del>Section 4.2.2<\/del> <span style=\"color: #0000ff;\">8.2.2 point j<\/span>) <del>Page 5<\/del> discusses training of operators with reference to,\u201demergency procedures to protect product quality, eg. Loss of HVAC system, loss of power etc\u201d.<\/li>\n<li><del>Section 4.2.3 Page 6 states<\/del> \u201c\u2026personnel, who require temporary access to the APA (aseptic processing area) shall be accompanied <em>at all times<\/em> by a person trained and qualified in accordance with 4.2.2\u2026\u201d\u00a0 <span style=\"color: #0000ff;\"><em>Similar wording now in 8.2.6<\/em><\/span><\/li>\n<li><del>Section 4.2.5 Page 6<\/del> <span style=\"color: #0000ff;\">8.2.7<\/span> All personnel that <em>directly<\/em> participate in the filling of manufacture of sterile products in the critical processing zones shall have taken part in a media fill that meets the requirements of this part of ISA 13408 at <em>least once per year<\/em>.\u201d<\/li>\n<li><del>Section 4.2.6 Page 6 states:<\/del> <span style=\"color: #0000ff;\">8.2.8<\/span>\u00a0 \u201cnew personnel\u2026shall take part in at least one\u2026media fill\u2026before being permitted to participate in processes carried out in critical process zones.\u201d<\/li>\n<li><del>Section 4.3 Page 6:<\/del> General employee health notes: Initial and periodic medical examinations should be performed for individuals assigned to aseptic processing. <em>8.4.1 &amp; 8.4.2 list general medical requirements.\u00a0 <a href=\"http:\/\/paulyeatman.net.au\/index.php\/2016\/08\/11\/notes-on-pics-guide-for-good-manufacturing-practice-for-medicinal-products-2009\/\" target=\"_blank\" rel=\"noopener\">The PIC\/s GMP guide<\/a> states something much like the above.<\/em><strong><span style=\"color: #ff0000;\"><br \/>\n<\/span><\/strong><\/li>\n<li><del>Section 4.4 Page 7\u2026\u201dmicrobiological monitoring program\u2026sampling of\u2026garments and gloves.\u201d<\/del>\u00a0 <span style=\"color: #0000ff;\">6.8.4.1\u00a0<\/span> Personnel trained and qualified to work in the APA shall be subject to routine microbiological monitoring programme.\u00a0 Monitoring data\u00a0 <del>Section 4.4.2 Page 7: \u201cresults of the (personnel) monitoring program<\/del> shall be used to identify trends and evaluate the need for retraining.<\/li>\n<\/ul>\n<p><strong>SECTION 9: GOWNING <\/strong><span style=\"color: #0000ff;\">Now 8.3 Gowning Procedures<\/span><strong><br \/>\n<\/strong><\/p>\n<p>Section 9.2 Gowning requirements<\/p>\n<ul>\n<li>Section 9.2.1 page 10: \u201cPersonnel shall wear dedicated factory clothing, <em>including<\/em> shoes, prior to entering the gowning area.<\/li>\n<li>Section 9.2.1 page 11 \u201cNOTE 2 Personnel may change into dedicated factory clothing in the airlock adjacent to the gowning area.&#8221;<\/li>\n<li>Section 9.2.2 page 11 \u201cNOTE A mesh hair net and beard cover, if required, are donned in the airlock. Disposable covers may be used <em>in addition<\/em> to dedicated shoes.<\/li>\n<li>Section 9.2.3 page 11 \u201cNOTE 2 After a garment has been tested for microbial contamination (see 4.4), it should not be worn in the APA until cleaned.\u201d<\/li>\n<li><em><span style=\"color: #0000ff;\">Substantial changes to text.\u00a0 Specifics about where to do what are not\u00a0 stated. \u00a0<\/span>\u00a0 I&#8217;d advise to stick to the above and\u00a0 you should pay attention to notes 1-3 in section 8.3.2.3. <\/em><\/li>\n<\/ul>\n<p><strong>SECTION 13 PROCESSING TIME <\/strong><span style=\"color: #0000ff;\">Now 9.2 Duration of the manufacturing process<\/span><strong><br \/>\n<\/strong><\/p>\n<ul>\n<li><del>Section 13.1 page 13: \u201cThe compounding of bulk solutions shall be controlled in order to prevent potential increase in microbiological levels, and possibly endotoxins, that can occur up to the time that the bulk solutions are sterile filtered.\u201d<\/del><\/li>\n<li><del>Section 13.2 page 13:<\/del> <span style=\"color: #0000ff;\">9.2<\/span> \u201cThe total time for the <del>product filtration and filling operations, and holding time after filtration and prior to filling<\/del> <span style=\"color: #0000ff;\">each unit operation of an aseptic process<\/span> shall be <span style=\"color: #0000ff;\">minimized and\u00a0<\/span> limited to a defined maximum.\u201d<\/li>\n<\/ul>\n<p><strong>SECTION 10 CLEANING AND DISINFECTION OF THE APA <\/strong><span style=\"color: #0000ff;\">Now spread through Sections 9.4 to 9.5<\/span><strong><br \/>\n<\/strong><\/p>\n<p>Section 10.1 Disinfectants and cleaning agents<\/p>\n<p><em>The need to validate and document is emphasized.\u00a0 Extensive changes to wording.<\/em><\/p>\n<ul>\n<li><del>Section 10.1.2 page 11: \u201cOnly cleaning agents and disinfecting agents which are <em>validated and approved<\/em> shall be used.\u201d\u00a0<\/del> <span style=\"color: #0000ff;\">No longer stated (as obvious?)<\/span><\/li>\n<li><del>Section 10.1.6 page 11: \u201cThe removal of disinfectant and cleaning agent residues on product contact surfaces shall be verified.<\/del>\u201d\u00a0 <span style=\"color: #0000ff;\">9.5.2 Cleaning of equipment discusses<\/span><\/li>\n<\/ul>\n<p><del>Section 10.2 Validation of disinfection procedures<\/del><\/p>\n<ul>\n<li><del>Section 10.2.2 page 12: \u201cEach facility shall have appropriate procedures in place to evaluate, approve and control the use of disinfectants.\u201d<\/del> Refer to 9.5.3 Disinfection of equipment<\/li>\n<\/ul>\n<p>Section 10.3 Monitoring effectiveness of cleaning and disinfection<\/p>\n<ul>\n<li>Section 10.3.3 page 12: \u201cWhen unusual microbial results are encountered or persist, an investigation to identify the source of contamination shall be performed and documented.\u201d\u00a0\u00a0<span style=\"color: #0000ff;\"> Now covered by 6.8 Environmental and personnel monitoring programmes<\/span><\/li>\n<\/ul>\n<p><strong>SECTION 17 MEDIA FILLS (PROCESS SIMULATION TESTS) <\/strong><span style=\"color: #0000ff;\">Now Section 10. Process Simulation <\/span><strong><br \/>\n<\/strong><\/p>\n<p>Section 17.2 Initial performance qualification<\/p>\n<p><em>Needs to cover\u00a0 all parts of the aseptic process and include all aseptic manipulations.\u00a0 Filter retentive capacity needs to be validated according to ISO 14208-2 and process simulation not intended to validate product (filter) sterilization.<\/em><\/p>\n<p>&nbsp;<\/p>\n<ul>\n<li><del>Section 17.5.1 page 18: \u201cMedia fill trials shall be conducted on separate days, at different times during the normal working period.\u201d<\/del> <em><span style=\"color: #0000ff;\">no longer stated.\u00a0<\/span> presumably as long as all shifts and worst case batch size (max) is covered, revalidation is acceptable.<\/em><\/li>\n<li><del>Section 17.5.2 page 18:<\/del> <span style=\"color: #0000ff;\">10.3.1<\/span>\u00a0 \u201cA list of permitted <del>and proscribed<\/del> intervention<span style=\"color: #0000ff;\">s shall be prepared and retained\u00a0<\/span><del> events&#8230;shall be available.\u201d<\/del><\/li>\n<li><del>Section 17.5.3 page 18:<\/del> <span style=\"color: #0000ff;\">10.3.1<\/span><del> \u201cMedia fill trials shall be conducted\u2026that include \u201cworst-case\u201d conditions\u2026\u201d<\/del><span style=\"color: #0000ff;\"> &#8230;as far as is reasonably practicable, include permissible worst case conditions.<\/span><\/li>\n<li><del>Periodic requalification \u2013 media-fill acceptance criteria: if &lt;500 unit per batch \u2013 3 media fills. If \u00b3500\u2013 1 media fill.\u00a0 Alert level = one contaminated unit in any unit.\u00a0 Investigate and repeat run (\u00b33000 units in batch, repeat run if values in Table 3 of ISO (located on page 21) are exceeded).\u00a0 Action level = two contaminated unit in a single run.\u00a0 Cease requalification, investigate and repeat initial qualification. (\u00b33000 units in batch, cease, investigate and repeat if values in Table 3 of ISO (located on page 21) are exceeded).\u00a0<\/del> <em><span style=\"color: #0000ff;\">Refer to Table 1 page 36 (10.9.2)<\/span><\/em><\/li>\n<\/ul>\n<p>&nbsp;<\/p>\n<ul>\n<li><del>Section 17.2.1 page 16:<\/del> <span style=\"color: #0000ff;\">10.5.1<\/span>\u00a0 \u201cPerformance qualification shall be conducted for each <del>new<\/del> aseptic <span style=\"color: #0000ff;\">processing operation<\/span>\u00a0 <del>filling line and<\/del> <span style=\"color: #0000ff;\">for each line and for each unique product<\/span><del> new product\/container<\/del> configuration <del>which<\/del> that has not been represented in a previous performance qualification.<\/li>\n<li><del>Section 17.2.2 page 16: \u201cPerformance qualification&#8230;Representative criteria include: the actual product\/container configuration\u2026two products which bracket all others\u2026products which have been deemed to be the worst case\u2026\u201d<\/del>\u00a0 <span style=\"color: #0000ff;\">See10.3.2 for new wording\u00a0 <\/span><\/li>\n<li><del>Page 17: Initial performance qualification&#8230;acceptance criteria: minimum of 3 media fills. Alert level = one contaminated unit \u2013 investigate cause and conduct one additional run (and repeat it if it fails); Action level = two contaminated units in a single run, or one each in two runs \u2013 cease qualification, investigate cause, repeat initial qualification.<\/del>\u00a0 <em><strong><span style=\"color: #0000ff;\">The number of simulation and the number of units filled per simulation are summarised in Table 1, as are the acceptance criteria.<\/span><\/strong><\/em><\/li>\n<\/ul>\n<p><del>Section 17.3<\/del> <span style=\"color: #0000ff;\">10.6<\/span> Periodic performance <span style=\"color: #0000ff;\">re<\/span>qualification<\/p>\n<ul>\n<li><del>Section 17.3.1 page 17:<\/del> <span style=\"color: #0000ff;\">10.6.1.1<\/span> \u201cScheduled\u2026requalification<del>s<\/del>&#8230;<span style=\"color: #0000ff;\">shall be conducted twice annually<\/span><del> at least every<\/del> <span style=\"color: #0000ff;\">approximately every <\/span>six months <span style=\"color: #0000ff;\">for each aseptic process and<\/span> <del>product\/container configuration and aseptic<\/del> filling line.\u201d<\/li>\n<\/ul>\n<p><del>\u00a0Section 17.4<\/del> <span style=\"color: #0000ff;\">10.7\u00a0<\/span> Repeat of initial performance qualification<\/p>\n<ul>\n<li><del>Section 17.4.2 page 18: \u201c<\/del>An aseptic process of filling line shall be subject to repeat performance qualification studies when:\n<ul>\n<li><span style=\"color: #0000ff;\">requilification has failed <\/span><del>an action level is exceeded<\/del><\/li>\n<li>production lines have not been in operation for an extended peri<\/li>\n<li>there has been a significant change<\/li>\n<\/ul>\n<\/li>\n<li><\/li>\n<li><del>Section 17.3.3 page 17:\u00a0<\/del> <span style=\"color: #0000ff;\">10.9.1<\/span> \u201cProduct manufacturing may resume while the media-filled units are being incubated; however, product release shall not occur until acceptable media-fill data are obtained.\u201d <span style=\"color: #0000ff;\">All product that has been produced on a line subsequent to the process simulation shall be quarantined until a successful resolution of the process simulation has occurred.<\/span><del>Section 17.5<\/del> <span style=\"color: #0000ff;\">10.3<\/span> <del>Media-fill<\/del> <span style=\"color: #0000ff;\">Simulation<\/span> procedures<\/li>\n<\/ul>\n<p><del>Section 17.6<\/del> <span style=\"color: #0000ff;\">10.2<\/span> Media selection and growth support <span style=\"color: #0000ff;\"><em>&lt;&lt;up to here&gt;&gt;<\/em><\/span><\/p>\n<p>S<del>ection 17.6.3 page 19:\u00a0<\/del> <span style=\"color: #0000ff;\">10.2.1<\/span> \u201cThe <span style=\"color: #0000ff;\">microbiological growth\u00a0<\/span> media selected for <span style=\"color: #0000ff;\">process simulation<\/span> <del>media-<em>fil<\/em><em>l<\/em><\/del> runs shall be capable of growing a designated group of reference<del> wide spectrum<\/del> of microorganisms and <del>of<\/del> supporting microbial recovery <del>and growth<\/del> of low numbers of microorganisms,<del> i.e.<\/del> 100 colony forming units (CFU)\/unit or less.<\/p>\n<p><del>Section 17.6.1 page 19:<\/del><span style=\"color: #0000ff;\"> 10.2.3<\/span> \u201cVerification of growth promotion media used in specific media-fill runs shall be conducted following the run.\u201d<\/p>\n<p><del>Section 17.6.2 page 19: \u201cThe incubation temperature shall be the same as that used for the media-filled units.\u201d <\/del><em><span style=\"color: #0000ff;\">No longer stated, but the logical incubation temperature.<\/span><\/em><del><br \/>\n<\/del><\/p>\n<p><del>Section 17.7<\/del> <span style=\"color: #0000ff;\">10.4<\/span> Incubation and inspection of media-filled units<\/p>\n<ul>\n<li><del>Section 17.7.1 page 19<\/del>: <span style=\"color: #0000ff;\">10.4.2\u00a0 <\/span>\u201c<span style=\"color: #0000ff;\">Units that are<\/span> leaking<span style=\"color: #0000ff;\">, broken<\/span> or<span style=\"color: #0000ff;\"> otherwise<\/span> damaged <del>media-fill evaluation units<\/del> <span style=\"color: #0000ff;\">to the extent that there is no question of their not being rejected during routine documented visual checking<\/span> shall be <span style=\"color: #0000ff;\">recorded and<\/span> removed,<del> and a record made of such removal, following processing and prior to incubation of the media.\u201d<\/del><\/li>\n<li><del>Section 17.6.2 page 19:\u00a0<\/del><span style=\"color: #0000ff;\"> 10.4.3<\/span> \u201cMedia-filled units shall be incubated<span style=\"color: #0000ff;\"> for not less than<\/span> <del>a minimum of<\/del> 14 days.\u201d\u00a0<em> Temp range stated here.<\/em><\/li>\n<li><del>Section 17.6.3 page 19: \u201cIncubation temperatures shall be appropriate for the specific growth requirements of microorganisms that are anticipated in the aseptic filling area.\u201d<\/del><\/li>\n<li><del>Section 17.7.4 page 19:<\/del> <span style=\"color: #0000ff;\">10.4.1<\/span> \u201cMedia-filled <span style=\"color: #0000ff;\">containers<\/span> <del>units<\/del> shall be <span style=\"color: #0000ff;\">agitated, swirled or inverted before incubation to ensure <\/span><del>stored or manipulated to allow<\/del> contact of the media with all <del>product contact surfaces in the unit.\u201d<br \/>\n<\/del><span style=\"color: #0000ff;\">interior surfaces of the container.<br \/>\n<\/span><\/li>\n<li><del>Section 17.7.5 page 19:<\/del><span style=\"color: #0000ff;\"> 10.4.4<\/span> <del>\u201cAfter\u2026incubation period\u2026media-filled containers\u2026visually inspected for\u2026microbial growth.\u201d<\/del> <em><span style=\"color: #0000ff;\">Now says to inspect via defined procedure.<\/span><\/em><\/li>\n<li><del>Section 17.7.6 page 19:<\/del> <span style=\"color: #0000ff;\">10.4.5<\/span> \u201cMicroorganisms <del>present in\u2026<\/del>units shall be identified\u2026\u201d<\/li>\n<li>\u201cNOTE 1 Inspection of the units at an earlier time period (3d to 7d incubation) can be useful to gain a preliminary indication of the results.\u201d<\/li>\n<li><del>\u201cNOTE 2<\/del> Media-filled units should be chronologically identified within the batch\u2026\u201d\u00a0<em><span style=\"color: #0000ff;\"> interestingly, no longer stated.\u00a0 Knowing at what point during the fill the contamination occurred is valuable information when investigating a process simulation failure as it could point to a specific simulated intervention.\u00a0 With that knowledge, one can examine batch records for the intervention and determine batch disposition of what may or may not be released batches (since last media fill).\u00a0 <strong>Nope, missed it.\u00a0 It&#8217;s in section 10.3.7.<\/strong><\/span><\/em><\/li>\n<\/ul>\n<p><del>Section 17.11<\/del><span style=\"color: #0000ff;\"> 10.5.3<\/span> <del>Media-fill runs exceeding action levels<\/del> <span style=\"color: #0000ff;\">Acceptance Criteria<\/span><\/p>\n<p><del>Section 17.11.1 Investigation<\/del><\/p>\n<ul>\n<li><del>Section 17.11.1.1 page 22: \u201cWhen\u2026action levels\u2026 exceeded\u2026 investigation\u2026 conducted and documented\u2026\u201d<\/del><\/li>\n<li><del>Section 17.11.1.2 page 22: \u201c\u2026action levels\u2026exceeded\u2026prompt review of all appropriate records relating to aseptic production between the current media fill and the last successful one.<\/del><\/li>\n<li><span style=\"color: #0000ff;\">10.5.3.2 Any contaminated\u00a0 unit shall result in an investigation to determine cause (if possible)<\/span><\/li>\n<\/ul>\n<p><del>\u201cThe investigation should include, but not be limited to, consideration of the following:<\/del> <em>no longer stated, though handy to make note of.<\/em><\/p>\n<ol>\n<li>Microbial environmental monitoring data<\/li>\n<li>Particulate monitoring data<\/li>\n<li>Personnel monitoring data (finger impressions, etc)<\/li>\n<li>Sterilisation cycles for media, commodities and equipment<\/li>\n<li>HEPA filter evaluation<\/li>\n<li>Room air flow patterns and pressures<\/li>\n<li>Operator technique and training<\/li>\n<li>Unusual events that occurred during the media fill<\/li>\n<li>Storage conditions of sterile commodities<\/li>\n<li>Identification of contaminants as a clue to the source of the contamination<\/li>\n<li>Housekeeping procedures and training<\/li>\n<li>Calibration of sterilisation equipment<\/li>\n<li>Pre and post-filter integrity test data, and\/or filter housing assembly<\/li>\n<li>Product and\/or process defects, and\/or limitation of inspectional processes; and<\/li>\n<li>Documented disqualification of samples for obvious reasons prior to final reading<\/li>\n<\/ol>\n<p><del>Section 17.9 Contamination with media<\/del><\/p>\n<p><del>\u201cContamination of the facility and equipment with media during the media-fill runs shall not compromise\u2026the facility and equipment or the product\u2026using the same facility and equipment.\u201d\u00a0<\/del> <span style=\"color: #0000ff;\">No longer be stated.\u00a0<\/span><em> Probably as cleaning procedures and line clearances should be validated and the process documented, so spilling growth media in a filling room will have a cleanup procedure, and you could always conduct a &#8220;VEM full screen&#8221; of a room after completion and cleanup of a process simulation.<\/em><\/p>\n<p><del>Section 17.10<\/del> <span style=\"color: #0000ff;\">10.8 Documentation of process simulations<\/span> <del>Data required for media fills<\/del><\/p>\n<p>\u201cAll <span style=\"color: #0000ff;\">process simulation<\/span> <del>media-fill<\/del> runs shall be fully documented, <del>and the following<\/del> information included\u2026:<\/p>\n<p><em>Words to this effect.\u00a0 Media fill replaced with process simulation; filling room with processing area, etc.\u00a0 A- Q, not numbered.<\/em><\/p>\n<ol>\n<li>date and time of media fill<\/li>\n<li>identification of filling room used<\/li>\n<li>container\/closure type and size<\/li>\n<li>volume filled per container<\/li>\n<li>filling speed<\/li>\n<li><del>filter lot and catalogue number<\/del> <span style=\"color: #0000ff;\">no longer stated <em>&#8211; would be in batch record as everything needs to be documented<\/em><\/span><\/li>\n<li>type of media filled<\/li>\n<li>number of units filled<\/li>\n<li>number of units rejected at inspection and reason<\/li>\n<li>number of units incubated<\/li>\n<li>number of units positive<\/li>\n<li>incubation time and temperature f<del>or each group of units incubated and whether any group of units is subjected to two different temperatures during the incubation<\/del><\/li>\n<li>procedures used to simulate any steps of a normal production fill, which might include, for example, mock freeze-drying or substitution of vial headspace gas<\/li>\n<li>microbiological monitoring data obtained during the media-fill set-up and run<\/li>\n<li>list of personnel who participated in the media-fill<\/li>\n<li>growth promotion results <del>of the media removed from filled containers<\/del><\/li>\n<li>identification of the microorganisms from any positive units, and investigation of any contamination events observed during media fills<em><span style=\"color: #0000ff;\"> split into two points <\/span><\/em><\/li>\n<li>management review<\/li>\n<li>length of time media was stored in holding tank prior to filtration <span style=\"color: #0000ff;\">no longer stated <em>&#8211; would be in batch record as everything needs to be documented<\/em><\/span><\/li>\n<li>length of time taken to fill all containers <span style=\"color: #0000ff;\">no longer stated <em>&#8211; would be in batch record as everything needs to be documented<\/em><\/span><\/li>\n<\/ol>\n<p><del><strong>SECTION 18 FINISHED-PRODUCT STERILITY TESTING <\/strong><\/del><span style=\"color: #0000ff;\">Now Section 11. Test For Sterility<\/span><strong><br \/>\n<\/strong><\/p>\n<p><del>Section 18.1 General<\/del><\/p>\n<ul>\n<li><del>Page 23:<\/del> <span style=\"color: #0000ff;\">11.1 General<\/span> \u201c<span style=\"color: #0000ff;\">Where<\/span> Sterility testing <span style=\"color: #0000ff;\">is required for<\/span> <del>of<\/del> aseptically filled products <span style=\"color: #0000ff;\">this testing<\/span> shall be conducted for each batch<del> or lot.<\/del>\u201d<\/li>\n<li><del>Section 18.2.1 page 23:<\/del><span style=\"color: #0000ff;\"> 11.2.1<\/span> \u201c<span style=\"color: #0000ff;\">Positive units from a test for sterility<\/span> <del>sterility-test results<\/del> shall be evaluated and an investigation shall be initiated\u2026\u201d<\/li>\n<li><del>Section 18.2.2 page 23:<\/del><span style=\"color: #0000ff;\"> 11.2.2<\/span> \u201cA correlation assessment between types of microorganisms found in the manufacturing environment, sterility testing room, and isolated from failed sterility tests shall be conducted.\u201d <em>says pretty much the same thing, though words moved around.<\/em><\/li>\n<\/ul>\n<p><del>Section 18.3 Sampling Plans<\/del><\/p>\n<ul>\n<li><del>Section 18.3.1 page 23: \u201cSampling plans\u2026developed to assure representation of the entire batch\u2026\u201d<\/del><\/li>\n<\/ul>\n<p><strong><del>SECTION 19 STEAM IN PLACE\u00a0<\/del> <\/strong><span style=\"color: #0000ff;\">Appears to have been removed entirely.\u00a0 Part 5 of ISO 13408 details Sterilization in place.<\/span><\/p>\n<p><span style=\"color: #0000ff;\">Some discussions on sterilisation using various methods is provided in Section 9. Manufacture of product<\/span><\/p>\n<p><del>Section 19.1 General<\/del><\/p>\n<ul>\n<li><del>Section 19.1.1 page 23: \u201cEquipment which cannot be sterilized in an autoclave\u2026shall be steam sterilised <em>in situ<\/em> with a demonstrated process lethality of six logarithms reduction\u2026\u201d<\/del><\/li>\n<li><del>Section 19.1.2 page 24: \u201cIn the absence of an automated SIP system, manual procedures shall be defined, adhered to, and documented.\u201d<\/del><\/li>\n<\/ul>\n<p><del><strong>SECTION 20 PROCESS FILTRATION\u00a0 <\/strong><span style=\"color: #0000ff;\">Appears to have been removed entirely.<\/span><\/del> <span style=\"color: #0000ff;\">Part 2 of ISO 13408 details filtration.<\/span><strong><br \/>\n<\/strong><\/p>\n<p><del>Section 20.1 Filter and filter equipment evaluation programme<\/del><\/p>\n<ul>\n<li><del>Section 20.1.1 page 24: \u201cA documented filter evaluation programme shall be established prior to validation and acceptance of filters.\u201d<\/del>\n<ul>\n<li><del>\u201cThe shedding of media-migration characteristics of the filter should be evaluated based on the intended life of the filter.\u201d<\/del><\/li>\n<\/ul>\n<\/li>\n<li><del>Section 20.1.2 page 24: \u201cProduct sterilizing filters shall be evaluated by an appropriate and defined challenge test, or evidence of product-specific data from the filter manufacturer shall be available.\u201d<\/del><\/li>\n<li><del>Section 20.1.3 page 24: \u201cAbsorption or adsorption the product by the filter shall be evaluated.\u201d<\/del><\/li>\n<\/ul>\n<p><del>Section 20.1.1 Biological Testing<\/del><\/p>\n<ul>\n<li><del>\u201cIf any plastics are used as components of filters\/filter systems, biological safety testing should be conducted on each plastic material.\u00a0 Testing may be conducted on the total filter\/filter system.\u00a0 Filters should be evaluated for the presence of endotoxins.\u201d<\/del><\/li>\n<\/ul>\n<p><del>Section 20.4 Filtration in the filling line<\/del><\/p>\n<ul>\n<li><del>Section 20.4.3 page 25: \u201cThe filter manufacturer\u2019s lot number shall be included in batch manufacturing records.\u201d<\/del><\/li>\n<\/ul>\n<p><strong><del>SECTION 21 FREEZE-DRYING<\/del> <\/strong><span style=\"color: #0000ff;\">Removed entirely.<\/span><strong><br \/>\n<\/strong><\/p>\n<p><del>Section 21.4 Process Routing<\/del><\/p>\n<ul>\n<li><del>\u201dFacility design related to location of equipment for filling, freeze-drying and sealing shall be such that transport of open product is kept to the minimum possible.\u201d<\/del><\/li>\n<\/ul>\n<p><span style=\"border-radius: 2px; 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Please consider a small donation so I can expand and improve on what I deliver.<\/strong><\/p>\n<p><input title=\"PayPal - The safer, easier way to pay online!\" alt=\"Donate with PayPal button\" name=\"submit\" src=\"https:\/\/www.paypalobjects.com\/en_AU\/i\/btn\/btn_donateCC_LG.gif\" type=\"image\" \/><img loading=\"lazy\" decoding=\"async\" src=\"https:\/\/www.paypal.com\/en_AU\/i\/scr\/pixel.gif\" alt=\"\" width=\"1\" height=\"1\" border=\"0\" \/><\/p>\n","protected":false},"excerpt":{"rendered":"<p>One of the main International Standards used as a reference document in a sterile pharmaceutical microbiology laboratory is ISO13408 &#8211; Aseptic Processing of Health Care Products .\u00a0 Long ago, I reviewed the 1998 edition.\u00a0 More recently, I acquired ISO 13208-1 (2008), so I compared my notes from the 1988 version with what is stated in [&hellip;]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[5,2],"tags":[12,40,35,20,25],"class_list":["post-380","post","type-post","status-publish","format-standard","hentry","category-documentation","category-the-regs","tag-guidelines","tag-iso","tag-standards","tag-sterile","tag-vem"],"_links":{"self":[{"href":"https:\/\/paulyeatman.net.au\/index.php\/wp-json\/wp\/v2\/posts\/380","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/paulyeatman.net.au\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/paulyeatman.net.au\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/paulyeatman.net.au\/index.php\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/paulyeatman.net.au\/index.php\/wp-json\/wp\/v2\/comments?post=380"}],"version-history":[{"count":23,"href":"https:\/\/paulyeatman.net.au\/index.php\/wp-json\/wp\/v2\/posts\/380\/revisions"}],"predecessor-version":[{"id":1216,"href":"https:\/\/paulyeatman.net.au\/index.php\/wp-json\/wp\/v2\/posts\/380\/revisions\/1216"}],"wp:attachment":[{"href":"https:\/\/paulyeatman.net.au\/index.php\/wp-json\/wp\/v2\/media?parent=380"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/paulyeatman.net.au\/index.php\/wp-json\/wp\/v2\/categories?post=380"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/paulyeatman.net.au\/index.php\/wp-json\/wp\/v2\/tags?post=380"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}