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v1.01© 2019 International Probiotics AssociationAll rights reserved. Any unauthorized copying, alteration, distribution, transmission, display or other use of this material is prohibited.

Probiotics are a unique food and dietary supplement ingredient. The World Health Organization defines these beneficial bacteria as“live microorganisms which when administered in adequate amounts confer a health benefit on the host.” As live microorganisms, probiotics require special handling and other considerations to ensure safety, quality and efficacy of finished products. The Good Manufacturing Practices (GMPs) for food and dietary supplements are written to cover a broad range of product categories with some level of flexibility that is needed and welcomed for various manufacturing environments provided the risk is controlled and reduced. Ultimately, the products must reach their established specifications. Therefore, the GMPs were not intended to particularly provide narrow details around the intricacies of manufacturing with probiotics. The probiotics industry is expanding rapidly, with many new entrants that may not be fully aware of the GMPs, let alone the special complexities involved in manufacturing probiotic products. As The Global Voice of Probiotics®, the International Probiotics Association (IPA) has developed these Manufacturing Guidelines as a tool to help finished product manufacturers and contract manufacturing companies identify considerations specific to manufacturing with probiotics, while providing some tips and guidance on achieving compliant products of high quality.

These guidelines are not to be considered all-encompassing with regards to regulatory and GMP requirements as set forth by the various regulatory authorities and recognized certifications. As such, they address only certain “typical” areas of possible concerns and therefore provide recommendations. It remains the manufacturers’ responsibility to build and demonstrate scientific rationales, and therefore information provided herewith serves only as examples, while providing opportunities for continuous process improvement.

Within the guidelines themselves, processes and practices are labelled as either Acceptable or Optimal. Acceptable practices should achieve probiotic finished products that are within specification assuming other GMP’s are adhered to during processing. In the spirit of continuous improvement and driving the industry forward, moving towards Optimal practices and processes should be the aim of probiotic powder finished supplement manufacturers which these guidelines cover. IPA feels it is critical to ensure that the quality of dietary supplement manufacturing is maintained across the board and to ensure that the integrity of the probiotic industry is protected.

INTERNATIONAL PROBIOTICS ASSOCIATION

PROBIOTICMANUFACTURINGGUIDELINES

The Global Voice of Probiotics®

© 2019 International Probiotics AssociationAll rights reserved. Any unauthorized copying, alteration, distribution, transmission, display or other use of this material is prohibited.

• Lactic acid bacteria (LAB) and yeast@ 2-8°C (36-46°F). • Spore bacteria @ <25°C (77°F). • Bulk dosage/Finished Goods (FG) @ 2-8°C (36-46°F).

Consult supplier recommended storage conditions as ultimate determinant.

• Lactic acid bacteria (LAB) @ < -20°C (-4°F)(frozen) or 2-8°C (36-46°F) depending of strain, real-time stability studies.• Yeast @ 2-8°C (36-46°F). • Spore bacteria @ <25°C (77°F). • Bulk dosage/Finished Goods (FG) @ 2-8°C (36-46°F).• All storage humidity controlled.


• USP 659 'Packaging and storage requirements'.


Probiotic Storage Storage locations

QUARANTINE PROCESS – INCOMING

• Ambient warehouse conditions. • Temperature <25°C (77°F) and RH <60%. • Driven by SOP's specific to receiving, handling, and testing of probiotics.• Based on supplier's recommendation.• USP General Chapter <659> - Packaging and Storage Requirements.

Temperature & Relative Humidity (RH) Control / Monitoring

Utilities & Equipment

• Probiotic raw materials must be shipped under conditions that will maintain the materials' integrity and specifications as recommended by the supplier. • Warehouse located in a manner that will allow for immediate transfer of quarantine materials to controlled conditions.

• USP <1079> Good Storage and Shipping Practices. • Health Canada Guide 0069.• WHO guidelines on good distribution practices.

Process Warehouse (Receiving Dock)

RECEIVING

• Real time stability conducted on actual finished product to match Finished Goods (FG) storage requirements - refrigerated (4°C) or room temperature (25°C). • Quantity of data required before launch could depend on country of sale.

• “ACCEPTABLE” + ICH conditions that are appropriate to marketed zones.• Supportive data can be used for upscaling in the same final packaging.

Stability Stability Rooms/Area

Test Chambers

• ICH Q5C Guidelines - Stability Testing of Biotechnological / Biological Products, USP General Chapter <659> (as in published IPA labelling guidance document), NSF White paper on stability (not specific to probiotics).• ICH Q1E - Evaluation of Stability Data• Any other condition or rationale to defend the relevant guidelines.

• Documented, calibrated and monitored. Not specific for probiotics, follow general GMP requirements.

• Trial should mimic scale up as much as possible and be run under similar environmental conditions.

• Pilot trials should be conducted on final formulas on equipment to be used for a commercial run at a minimum quantity as appropriate; in general 10% of the final commercial quantity of the finished supplement is typically considered. • Test typical physical parameters plus potency loss in processing. In situations where the formulation in this specific process is already known and properly controlled, pilot trials may not be necessary.

Tooling & Equipment Capabilities

Small-Scale Pilot & Manufacturing Facility

• Minimum effective dosage incorporated with suitable overage to ensure end of shelf life viability• Consideration for ingredients that may negatively impact stability (ie. Water activity, antimicrobial activity, moisture, etc).• Appropriate packaging to protect from moisture, oxygen, light, etc. as appropriate to the product.

• Rationale for individual species or combinations. • “ACCEPTABLE” + supporting documentation. Product Formulation Assigned Area

PRODUCT DEVELOPMENT / PILOTING

• Topic not unique to probiotics but rather standard cGMP's. US FDA 21 CFR 111, NNHPD in Canada, TGA, etc.• If it is under electronic environment, then 21 CFR 11.

Documentation & Traceability

Batch Records, SOPs, Systems

• Process controls established (e.g. principles based on HACCP or HARPC) verification of control points, calibrations, air quality and other utility systems having a potential impact on the product.• Water quality must be tested according to applicable specifications. Cleaning verification for residue and carry-over (ex. ATP).• Scientifically valid and verified analytical methods. • Changes to manufacturing, packaging, labelling, quarantine or other operations are to be approved by Quality via an established Change Control process.

• “ACCEPTABLE” + IQ / OQ / PQ equipment and process validation when required by regulation or based on risk assessment, using whenever possible, compendial analytical methods. • Written procedures for cold storage requirements and calibrate all equipment used to measure or regulate, according to risk.

• By SOPs, certified standards, and compendial methods. Example - TGA resource for rationale when appropriate validation is advised.• Validation gudelines issued by authorities like TGA, FDA, Health Canada, MHRA, etc.

Verification & when appropriate Validation – Process, Utilities, Equipment, Cleaning, Analytical

Systems

• Cleaning practices are in place to avoid contamination (minimize the risk). In the case of probiotics, special consideration needs to be considered due to the high levels of Total Viable Cell count (TVC).

• Cleaning practices are submitted to a cleaning validation with routine monitoring. • All environmental factors such as air handling, staff hygiene/PPE, building design, clear procedures and cleaning verification tools need to be considered.

• Depends on contamination of microorganism, cleaning practices, etc.

Cross Contamination QC

• The most common contaminants (Total aerobic bacteria, yeast and molds, coliforms, etc.) are monitored on surfaces, air, and as appropriate based on local regulations.

• “ACCEPTABLE” + specifying set limits as is established by a risk analysis. Further analytical testing may include strain identification and origin.

• One example - Control of Listeria monocytogenes in RTE Food - Draft Guidance.

Environmental Monitoring (Micro)

QC

• Monitored, established limits in various stages of storage and production.

• 24/7 alarmed monitoring on all storage and production suites, remote access.


Utilities, Storage & Equipment

• Established number of air changes per hour with filtration on feed air, heating and cooling air, dehumidification (product in powder form) and exit air where product is exposed.

• Monitoring and controlling conditions, established number of air changes per hour with terminal HEPA filters in areas where product is exposed, ensuring that the pressure differential is set and monitored accordingly.

• ISPE.• Annex 5 - Supplementary guidelines onGMP practices for heating, ventilation and air-conditioning systems for non-sterile pharmaceutical dosage forms.

HVAC / HEPA System Facility Utilities

MANUFACTURING FACILITY – GENERAL

GUIDELINES CONTINUE ON BACK

STAGE LOCATION ACCEPTABLE PROCESS OPTIMAL PROCESS (BEST PRACTICES) RECOMMENDED GUIDANCES

PROBIOTIC MANUFACTURING GUIDELINES

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• Optimal water activity (Aw) ranges are established via process qualifications and stability studies. Acceptable Aw of blend can vary depending on stability of the probiotic strains, final packaging chosen, excipients, other active ingredients, etc.

In general, Aw of the final blend containing any lactic acid bacteria should be less then <0.25 or per supplier's recommendations based on formulation and process. Ultimately, Aw and stability should be part of the formulation development process.

Water Activity (Aw) Lab

• Minimize with tight scheduling. • Pull through system to limit exposure time. Maximum hold time is qualified and proper storage practices during hold time are maintained and detailed.

Hold Time • Storage Area• Manufacturing Facility

• <25°C (<77°F) & <50% RH. • 22.2°C (<72°F) & <40% RH. • Low shear blending preferred to minimize temperature increases and activity loss. Ultimately suppliers' recommendations in this portion of the manufacturing process should be adhered to if available.• Temperature and relative humidity are related, some processes need to be optimized adjusting one or the other for the best possible quality and processibility.


Facility Utilities

BLENDING (& SCREENING AS APPROPRIATE)

• Tempering of frozen / refrigerated active ingredients until fully to room temperature before opening.• Weigh, dispense and record per cGMPs, should include verification.

• Tempering duration will vary depending on size of bulk and type of packaging.

Probiotics Dedicated room for activity

WEIGH / DISPENSE

• In accordance with local regulatory requirements.Active Ingredients, Excipients, Dosage Form Components, Packaging Components

Assigned Storage Area

• Lactic acid bacteria (LAB) and yeast@ 2-8°C (36-46°F). • Spore bacteria @ <25°C (77°F). • Bulk dosage/Finished Goods (FG) @ 2-8°C (36-46°F).


• Lactic acid bacteria (LAB) @ < -20°C (-4°F)(frozen) or 2-8°C (36-46°F) depending of strain, real-time stability studies.• Yeast @ 2-8°C (36-46°F). • Spore bacteria @ <25°C (77°F). • Bulk dosage/Finished Goods (FG) @ 2-8°C (36-46°F).• All storage humidity controlled.


• USP 659 'Packaging and storage requirements'.


Probiotics Storage locations

RELEASED MATERIALS WAREHOUSE

• Maintain enough product to allow for two sets (optimal: 3 sets or as specified in regulation) of analytical tests and store according to suppliers' recommendations in a locked and secure area. • Retains are to be kept at least 1 year past the expiry date of the culture.

• 21 CFR 111, NNHPD & TGA or reference other applicable/local regulations.

Retains Retain Areas

• Read and record upon receipt. In general, Aw of incoming probiotic cultures should be less then <0.2 or per supplier's recommendations based on strains and process. In any event, probiotics are formulated based on their real-time stability.

• Spore forming and yeast probiotics could yield a higher water activity and should be formulated based on real-time stability.• USP <922> - Water Activity.

Water Activity (Aw) Lab and/or External Lab

• Per regulations (e.g. lead, mercury, arsenic, copper, cadmium). • USP <2232> - Elemental Impurities.• Prop 65 if applicable.

Heavy Metals Lab and/or External Lab

• Per probiotic suppliers' specificationsNon-lactics for LAB's Lab and/or External Lab

• Per regulations (e.g. salmonella, e-coli, coliforms, staph, etc.). • Additional testing could be required depending on the population intended for the finished product to be manufactured. Possible reference is November 2016 IPA ISAPP Probiotic Usage in High Risk Population Guidelines.

Pathogens Lab and/or External Lab

• CFU for total enumeration plate counts. • “ACCEPTABLE” + for incoming pre-blended probiotic blends, CFU for genus per plate counts when proper methods are available to selectively enumerate.

Enumeration Lab and/or External Lab

• Species ID (e.g. PCR, 16sRNA, etc.). Forward and reverse primer for low replicate regions. • When it is necessary to prove safe strain lineage, strain level ID should be utilized (i.e. Enterococcus faecium, E. coli, etc.); or should be covered by your vendor qualification program.

• “ACCEPTABLE” + Strain ID where available (e.g. PCR, PFGE, RAPD, antibodies, etc.). For PCR, multiple primers for low replicate (unique) regions.

• Currently, the readily available technlogy exists for single strain products and is in development for less complex incoming blends of probiotic strains.

Microorganism(s) ID Lab and/or External Lab

QC TESTING OF INCOMING CULTURES


• Needs to match the processing conditions when probiotic powder is exposed per the processing steps below. • Ultimately driven by the risk assessment made with probiotic type and supplier's recommendations.

Sampling Area

INCOMING QC INSPECTION & SAMPLING


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• Maintain enough product to allow for at minimum two sets of analytical tests (optimal: 3 sets or as specified in regulation) and store according to finished products' storage recommendations in a secure area.• Retains kept 1 year past the expiration date or 2 years past the date of last distribution or per local regulations.

• 21 CFR 111, NNHPD & TGA or reference other applicable/local regulations.

Retains Retain Areas

• Read and record upon receipt. • “ACCEPTABLE” + Monitor at multiple stages throughout process.

In general, Aw of the final product containing any lactic acid bacteria should be less then <0.25 or per supplier's recommendations based on strains and process. In any event, probiotics are formulated based on their real-time stability.

• Spore forming and yeast probiotics could yield a higher water activity and should be formulated based on real-time stability.• USP <922> - Water Activity.

Water Activity (Aw) Lab and/or External Lab

• Per regulations (e.g. Lead, Mercury, Arsenic, Copper, Cadmium, etc.). • USP <2232> - Elemental Impurities.Heavy Metals Lab and/or External Lab

• Per probiotic suppliers' specifications. Non-lactics for LAB's Lab and/or External Lab

• Per regulations (e.g. salmonella, e-coli, coliforms, staph, etc.). • Additional testing could be required depending on the population intended for the finished product at hand. Possible reference is November 2016 IPA ISAPP Probiotic Usage in High Risk Population Guidelines.

Pathogens Lab and/or External Lab

• CFU for total enumeration such as classical plate counts. Enumeration (CFU) Lab and/or External Lab

• Demonstrate full traceability throughout the manufacturing process.

• “ACCEPTABLE” + Species ID where available and when possible per appropriate method (e.g. PCR, PFGE, RAPD, antibodies, etc.). Multiple primers for low replicate (unique) regions.

Microorganism(s) ID Lab and/or External Lab

QC TESTING OF FINISHED PRODUCTS

• <25°C (<77°F) & <50% RH. • <22.2°C (<72°F) & <40% RH.Capsule & Tablet Bottling and Blistering

Packaging Facility / Area

• <25°C (<77°F) & <50% RH. • <22.2°C (<72°F) & <40% RH.Powder Bottling, Stick Sachet, and Sachet (Powder Exposed to Environment)

Packaging Facility / Area

• Ensure packaging component specifications are established with the required stability (conditions and duration) in mind and that it is verified with long term stability study.

In general, check with your supplier to ensure temperature & relative humidity recommendations are applicable.

PACKAGING

• Minimize hold times between dosage manufacturing and finished packaging in general with tight scheduling. • <25°C (<77°F) and <50% RH if held for no more than 48 hours in sealed container.

• Minimize hold times between dosage manufacturing and finished packaging in general with very tight scheduling.• <4°C (<39.2°F) and <50% RH if finished packaging completed in more than 24 hours.

• Controls and monitoring are to be put in place to keep established and suitable temperatures and relatvie humidities; installing, calibrating and maintaining with measuring or recording devices as necessary to ensure accuracy.



• Storage Area• Facility Systems

BULK DOSAGE FORM STORAGE

• Dosage specific. Others Manufacturing Facility

• <25°C (<77°F) & <50% RH. • <22.2°C (<72°F) & <40% RH.Chewables Manufacturing Facility

• <25°C (<77°F) & <50% RH. • <22.2°C (<72°F) & <40% RH.Tablets Manufacturing Facility

• <25°C (<77°F) & <50% RH. • <22.2°C (<72°F) & <40% RH.Capsules Manufacturing Facility

• Controls and monitoring are to be put in place to keep established and suitable temperatures and relative humidities; installing, calibrating and maintaining with measuring or recording devices as necessary to ensure accuracy.


DOSAGE FORM MANUFACTURING

• <25°C (<77°F) & <60%RH acceptable with minimized delay between blending and dosage manufacturing (in general <48 hours).

• <4°C (39.2°F) and <50% RH if delay between blending and dosage manufacturing longer than 48 hours.• If held refreigerated, tempering should be conducted.

• Segregated to prevent mix-up and cross contamination. USP <1079>; USP <1118>. In general storage should not inadvertantly affect product quality and shelf life.




INTERMEDIATE BLENDS STORAGE



• Bulk dosage and Finished Goods (FG) @ <2-8°C (36-46°F) or per supplier recommendations. • Temperature & RH are controlled ultimately as per shelf life conditions. Requirement may vary if contains only spore bacteria or a non-powdered format for example.


Storage Warehouse and/or Coolers

QUARANTINE PROCESS - FINISHED PRODUCT IN QC TESTING


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• Finished product containing lactic acid bacteria should be shipped under refrigerated conditions (reefer) unless the season and destination remain <10°C (<50°F) and transit time is minimized.

• Finished product containing lactic acid bacteria should be shipped under refrigerated conditions (reefer) and transit time be minimized. • Monitoring devices used in outgoing shipments for receiving party to analyze shipment conditions are in line with products' stability profile (e.g. data loggers, truck printout, etc.). Put in place agreements with shipping companies to ensure conditions are maintained.

• Good Shipping & Receiving Practices.

In general, shipping process and conditions should account for the season of the year, the destination and the documented stability of the product being transported.

Shipping Conditions Truck

• Separate shipping and receiving areas that are controlled by SOP to maintain clean proper area control.• Staging process should be designed to minimize the time between product removal from storage and loading for transportation. • Environmental condition of the staging area should be per your local GMPs.

• Good Shipping & Receiving Practices.Physical Location Warehouse (Shipping Dock)

SHIPPING

• <25°C (<77°F) if shipped within 48 hours of final packaging completion. Otherwise, <4°C (<39.2°F).

• <4°C (<39.2°F) and 50% RH until shipment. Finished product storage should ultimately reflect at minimum labeled storage conditions.

• Temperature & RH are controlled ultimately as per shelf life and recommended storage conditions. Requirement may vary if contains only spore bacteria or a non-powdered format for example.




FINISHED PRODUCT STORAGE



Phone +1 514 571 5949

Online [email protected] www.internationalprobiotics.org

CONTACT

Address 1824 S Robertson Blvd Los Angeles, CA 90035 United States

LIMITATION OF LIABILITYIN NO EVENT WILL IPA BE LIABLE TO ANY PARTY FOR ANY DIRECT, INDIRECT, INCIDENTAL, SPECIAL, CONSEQUENTIAL OR PUNITIVE DAMAGES FOR USE THESE GUIDELINES, WITHOUT LIMITATION, LOST PROFITS OR REVENUES, COSTS OF REPLACMENT PRODUCTS, BUSINESS INTERRUPTIONS, LOSS OF DATA OR DAMAGES RESULTING FROM USE OF OR RELIANCE ON THE INFORMATION HEREIN.

In some jurisdictions, limitations of liability are not permitted. In such jurisdictions, the foregoing limitations may not apply to you.

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