ATP-IQPCWorkshop_2010v2 Cadena de Frio gap

Cold Chain

1. How to perform an efficient Cold Chain
Compliance and Gap Analysis ?
Workshop
IQPC 2010 Philadelphia

2. COLD CHAIN
REGULATIONS & GUIDELINES
Summary
Thepharmaceuticalcoldchainconceptimpliesallnecessarymeanstomaintain
therapeuticproductsinthespecifiedmanufacturer’stemperaturelimitsduringallthe
logisticanddistributionprocess(manufacture,storage,transportation,finaluse).
Thecoldchaincomplianceandgapanalysisistheveryfirststeptoevaluatethe
complianceofyouroperationsandlogisticsinregardtotheregulatorycontext.Therespect
ofthecoldchaininitiallyimpliestoknowwellconstraintswhichsurrounditandtrapstobe
avoided.
–How to prepare a cold chain regulatory gap analysis?
–What should be covered when looking at cold chain compliance?
–Gap analysis: a first step to develop a cold chain compliance program.
–What are the requirements for the storage and distribution of Drug products?
–How are shared the responsibilities for a good cold chain compliance?

3. COLD CHAIN
REGULATIONS & GUIDELINES
•Food and Drug Administration(FDA):
–CFR 205: «Guidelines for State Licensing of Wholesale Prescription Drug Distributors»;
–CFR 211: «Current Good Manufacturing Practice for Finished Pharmaceuticals».
•Food and Drug Administration(FDA):
–“ Draft Guidance for Industry, Stability Testing of Drug Substances and Drug Products”, June
1998; International Conference on Harmonization (ICH), “Guidance for Industry, Q1A(R2):
Stability Testing of New Drug Substances and Products”, November 2003.
•United States Pharmaceopaedia:
–Chapter 1079: «Good Storage & Shipping Practices»; Chapter 1118: «Monitoring Devices-
time, temperature and humidity »; Chapter1077: «Good packaging practices ».
•Parenteral Drug Association:
–PDA Technical Report No39, revised 27: «Guidance for temperature-Controlled Medicinal
Products: Maintaining the Quality of Temperature-sensitive medicinal Products through the
Transportation Environment» (Suppl., vol. 61, no S-2).
•Health Distribution Management Association (HDMA):
–«Guidelines for Managing Cold Chain & Temperature Sensitive Products » (2009).
•Health Canada (HPFB Inspectorate):
–«Guide 069, Guidelines for temperature Control of Drug Products during Storage and
Transportation »; Date Issued: October 17, 2005.

4. COLD CHAIN
REGULATIONS & GUIDELINES
•International Safe Transit Association (ISTA)
–Test Procedure 5B: Focused simulation guide for thermal performance testing of temperature
controlled transport packaging.
–Test procedure 7D: Thermal controlled transport packaging for parcel delivery system
shipment.
–ISTA 7E + Standard 20.
•American Society for Testing and Material (ASTM)
–Standard Test Method D 3103-99: Thermal insulation quality of packages.
•International Conference on Harmonization (ICH)
–Note for guidance on stability testing: stability testing of drug substances and products (ICH):
CPMP/ICH/2736/99 (revision of ICH/380/95).
•International Air Transport Association (IATA)
–Time and Temperature Task Force (TTTF); « The Perishable Cargo Regulations manual »
•Cold Chain Committee
–Guidelines for shippers and transport service provider’s partners involved in the distribution of
pharmaceutical products registered for storage between 2°C and 8°C.
–Guidelines for the development of insulated shipping containers to ensure the quality of
products witch have registered conditions between 2°C and 8°C.

5. ADDITIONAL REGULATIONS
Additional Regulations that may impact the Storage and Distribution
of Drug products.
General Security / Anti-counterfeting
•National Association of Boards of Pharmacy (NABP):
–Verified-Accredited Wholesaler Accreditation (VAWD).
•State Regulations (State Board of Pharmacy):
–Pharma Distribution, Licence, Pedigree.
•Transportation Security Administration (TSA):
–Screening of Cargos (Air, Sea, Ground); Title 49 of the Code of Federal Regulations (CFR),
Chapter XII, parts 1500 -1699.
–DEPARTMENT OF HOMELAND SECURITY, Transportation Security Administration, 49 CFR
Parts 1520, 1540, 1542, 1544, 1546, and 1548, «Air Cargo Security Requirements».
•US Department of Transportation

6. COLD CHAIN
REGULATIONS & GUIDELINES
US FDA: Adulterated Drug Products, FD & C Act Chapter V, sec.501.
•Sub-chapter A, (2)(B) states:
"A drug or device shall be deemed adulterated -ifthe methods used in, or the facilities or
controls used for, its manufacture, processing, packing, or holdingdo not conform to or are
not operated or administered in conformity with current good manufacturing practice to
assure that such drug meets the requirements of this Act as to safety and has the identity
and strength, and meets the quality and purity characteristics, which it purports or is
represented to possess.«
•The use of the term holdingis an interesting one. "Holding" of a drug occurs when the
drug is being distributed, transported, warehoused or stored.
•"Storage (holding) of a drug at appropriate temperatures and under appropriate conditions
is a requirement" within current Good Manufacturing Practices (cGMP). Code of Federal
Regulations Title 21, Sub-chapter C, Part 205 Sec. 205.50(c)

7. PRINCIPLES
•The good quality of Drugs must be maintained throughout distribution
networks. Thus, these products will reach the hospital, and therefore the
consumer, without any deterioration of their therapeutic properties.
•The Quality Control service must make sure that conditions of storage are
observed at any moment, including transport.
•Standardized Operation Procedures (SOP) should describe all operations
likely to affect the quality of Drugs or the distribution, including the reception
of deliveries, storage and recording of storage conditions.
•Instruments and equipments used should be adequate to ensure a good
conservation and distribution of Drugs.

8. Aspects to analyse for a complete
Cold Chain Compliance
•Staff members
•Documentation
•SOPs
•Reception area
•Storage area
•Monitoring of storage area
•Transportation of drug products
•Monitoring of temperature in transport
•Returned products
•Returned of non defective products
•Emergency plan/drug products recall
•Quality agreements

9. STAFF MEMBERS
•Has your personal been trained to specific Cold Chain Regulations and SOPs and
related tasks?
•Did the management of your company was also trained?
•Did all operational resources has been trained to their specific tasks?
•Was all training documented and logged?
•Is all related documentation is up to date?
•Staff members should be trained with the principles of the GMP/GDP relating to their
tasks.
•Trainings should be ensured by qualified personal.
•Trainings should be in conformity with a written established program and training
activities should be consigned in files.
•The effectiveness of the continuous training should be evaluated periodically.
•Training should be offered before any application of a new or modified SOP.
•Staff working in areas where active, toxic, infectious or sensitizing products are
handled, should receive a specific training for this purpose.

10. STAFF MEMBERS
Note:In conformity with the FD&C Act and GMPs:CFR part 211, Sec. 211.25 Personnel qualifications;
CFR part 205, Sec. 205.7 Personnel; USP 1079, General Chapters, PERSONNEL TRAINING
Regulation
Compliance
Recommandations
123U
Staff members are trained to GMP principles
related to their respective tasks .
The training is provided by qualified persons, in
relation with their function.
Training sessions comply with a predefined
training program; this program is written and all
training is consigned in files.
The efficiency of the continuous training is
periodically evaluated.
Training is offered prior to any application of new
or modified standardized operational procedures
(SOPs).
Workers located in areas where highly active,
toxic, infectious or sensitizing products are
handled receive a specific training.
1: not compliant 2: weakly compliant 3: ongoing U: undetermined

11. DOCUMENTATION
–Are shipping documents complete?
–Are storage conditions documented?
–Is all documentation complete and include all regulations aspects?
–Do you document all out-of-specs?
–Do you have Quality agreement with your subcontractors?
•Storage and shipping conditions must prevent any deterioration of the content, purity
and physical characteristics of Drugs.
•In order to show that these conditions are respected, standardized operation
procedures (SOPs) and shipping / reception registers are available:
–Transport and storage documentation
–Approved shipping documentation for the products forwarding.
–Evidences demonstrating that shipping requirements were respected (temperature control).
–Drugs production documentation.
–Documentation attesting that drug manufacturing, packaging, labelling, analyze and storage
conditions are in conformity with Good Manufacturing Practices requirements.
–Documentation attesting that the duration during which the drug, placed in the container in
which it is sold, will remain in conformity with the specifications.

12. DOCUMENTATION
Cont’d
–Documentation attesting that the duration during which the drug, placed in the container in which it
is sold, will remain in conformity with the specifications.
–Files on each Drug batch sale or manufacturing should be kept.
–In Reception/Shipping documentation are described : Drugs description; Quantity; Name and
addresses of the recipient; Name and Addresses of the shipper; Batch number; Drug scratch date;
Shippingdate.
–All documentations should be available on request from authorities.
–All registers relating to transport, including those of monitoring, should be kept at least a year after
the expiry date of the product. The statements of temperature should be available for examination.
–Registers containing data relating to investigations and interventions at the time of variations in the
temperature compared to the fixed parameters, are kept at least a year after the expiry date of the
product.
–When conveyors are retained, all conditions should be stipulated in a contract written between the
distributor and the third party. All the subcontractors should then conform to the applicable
requirements.

13. DOCUMENTATION
Note:In conformity with the FD&C Act and GMPs:CFR part 211, Sec. 211.196 Distribution records; CFR part 205,
Section 205.50;
Regulations
Compliance
Recommandations
123U
The transportation and warehousing documents (including
cautions and/or warnings for the shipping of the final
products).
The documentation for approved transportation conditions.
Evidences demonstrating that all shipping requirements have
been fulfilled (temperature regulation, documentation for
containers qualification, etc.).
The documentation attesting that drug manufacturing and
warehousing conditions comply with the Canadian GMP
requirements.
The documentation attesting that the length of time, when the
product is in the package in which it will be sold; will comply
with the specifications established for the product.
The documentation evidencing that drug products have been
warehoused handled and transported in compliance with
predefined conditions (temperature, etc). These conditions
must be supported by stability reports*.
Records of lots manufacturing and sales are kept.
1: not compliant 2: weakly compliant 3: ongoing U: undetermined

14. DOCUMENTATION
Note:In conformity with the FD&C Act and GMPs:CFR part 211, Sec. 211.196 Distribution records; CFR part 205,
Section 205.50;
Standard
Compliance
Recommandations
123 U
Receiving/shipping documentation includes following data:
The drug description;
The quantity;
The name and address of the recipient;
The name and address of the shipper;
The lot number;
The expiration date of the drug;
The shipping date.
Transportation records are maintained, including monitoring
records where applicable, for a period of one year after
expiry date. They are available for inspection
Records of investigations and actions taken in the event of
excursions outside the labelled storage conditions are kept
for a minimum of one year after the expiration date of the
product.
When commercial carriers are used, all pertinent conditions
(including warehouse and transportation activities) are
specified in a written contract and the generated
documentation is periodically controlled. Records of
inspection are kept and all deviations lead to further
investigations.
1: not compliant 2: weakly compliant 3: ongoing U: undetermined

15. –Are all SOPs on Cold Chain are written and available?
–Are they complete and cover all aspects of Cold Chain regulations ?
–Are they signed and approved ?
•All Cold Chain SOPs should be written and included on your QA system.
•It is the company’s responsibility to write SOPs, implement them, train employees,
approve and secure them and document all training activities
•The SOPs must be available at all time and review periodically. They have to be
signed and approved by the QA manager.
STANDARDIZED OPERATING PROCEDURES

16. STANDARDIZED OPERATING PROCEDURES
Note:In conformity with the FD&C Act and GMPs:CFR part 211, Sec. 211.100 Written procedures; deviations; CFR part
211, Sec. 211.142 Warehousing procedures; CFR part 205, Section 205.50; USP 1079, General Chapters
SOP
Compliance
Recommandations
123U
Warehousing Methods for Drug Products (including the drug
products that require specific warehousing conditions)
Drug orders and shipments preparation (including a
description of the shipping configuration of the protective
package used, and taking into consideration the
requirements for labelling, sealing and warning for the
shipping/warehousing).
Use of equipment and instruments related to the cold chain
(refrigerator, cold room, controllers…).
Calibration of monitoring and regulation instruments
dedicated to cold chain equipments.
Corrective actions in case of unfavourable events during the
drug products transportation under cold chain.
Verification of the drug product condition and labels in the
receiving areas (required verifications to ensure that the
containers have not been opened).
Stocks management, including stocks that require a specific
warehousing.
Labelling policy
1: not compliant 2: weakly compliant 3: ongoing U: undetermined

17. STANDARDIZED OPERATING PROCEDURES
Note:In conformity with the FD&C Act and GMPs:CFR part 211, Sec. 211.100 Written procedures; deviations; CFR part
211, Sec. 211.142 Warehousing procedures; CFR part 205, Section 205.50; USP 1079, General Chapters
SOP
Compliance
Recommandations
123U
Cleaning and maintenance of warehousing and sampling
areas.
Stocks safety
Verification of delivery and shipping bonds.
Corrective actions when the temperature derives from the
labelled warehousing temperature parameters during drug
product warehousing.
Stocks handling after their expiration date.
Handling of damaged stocks.
Management of drug products in quarantine.
Actions to be taken at the drug products return.
1: not compliant 2: weakly compliant 3: ongoing U: undetermined

18. Topics to be included in SOPs
Calibration
Cleaning
Mapping of storage area
Monitoring of storage area
Preventive maintenance of thermal equipment
Alarm management
Operation of thermal equipment
Temperature monitoring in transport
Qualification of thermal equipment
Qualification of transport system
Alarm verification and tests
Storage and transport conditions management
Operation and maintenance of monitoring system
Operation and maintenance of data logger
management system
Storage of drugs
Manipulation of drugs
Complaints
Return of defective products
Data loggers management system
Expired products
Returns
Quarantine
Stock management
Inspection
Drug products transportation
Drug products in transit
Out-of-specs
Shipping of drugs
Shipping and reception bonds/drug verification
Order preparation
Reception of drugs
Packaging methods
Labelling

19. RECEPTION / STORAGEAREA
-Do you have systems to control the temperature and humidity in your storage area (HVAC
system)?
–Are thermostats secure not to have access to change set-points by unauthorised personal?
–Is your racking far enough from doors in order to protect your products from out-of-specs?
–Did you perform mapping of all your storage area in winter and summer?
•The reception area should protect deliveries from bad weather, during the unloading of
Drugs.
•The entry of the reception zone must be separated from the storage area.
•Reception and shipping area should not allow a direct access to the production area.
•Precautions should be taken to prevent unauthorized people to enter storage area.
•Storage area should be cleaned and frequencies of cleaning should be documented.
•Areas where Drugs and returned products are placed in quarantine should be clearly
identified and their access should be limited to the authorized staff.
•Storage areas should be sufficiently enlightened to facilitate all operations of storage.
•The temperature and moisture (if necessary) should be controlled, so that, raw materials,
finished products, samples and standards of reference are not faded.
•Special conditions (of temperature, moisture, light, etc) necessary for the storage of
products in transit should be set up. Check-outs should be carried out and
documentation should be available.

20. –Are all sensors and probes calibrated once per year?
-Are all equipment identified?
-Are all employees been trained to storage related SOPs?
-Are all equipement files available?
-Are all critical components of equipment identified?
-Is temperature distribution inside equipment in the range?
•Instruments and devices used to monitor and regulate the temperature are calibrated
at least once a year.
•Analyses of the temperature distribution in warehousing areas dedicated to
temperature sensitive products are performed. The uniformity of the temperature
distribution is demonstrated (Equipment Qualification).
•All Storage equipments should be identified. Critical components of storage
equipment should be identified. Each equipment should have an up-to-date file that is
readily available. Maintenance program should be in place for storage equipment.
•Storage in equipment should be covered by a specific SOP.
STORAGE EQUIPMENT

21. RECEIVING AREA
Note:In conformity with the regulations/standards below: USP 1079, General Chapters
Regulation/Standard
Compliance
Recommandations
123U
During their unloading, drug products are protected from bad
weather conditions.
The entrance of the receiving area is clearly segregated from
the warehousing area.
Receiving and shipping areas do not allow a direct access to
the production area.
The drug products are promptly transferred to an appropriate
warehousing area.
1: not compliant 2: weakly compliant 3: ongoing U: undetermined

22. WAREHOUSING AREA
Note:In conformity with the regulations/standards below: CFR part 205, Sec. 205.50; USP 1079, General Chapters
Regulation/Standard
Compliance
Recommandations
123U
Cautions are taken to avoid that any non-authorized
individuals enter warehousing areas.
The cleaning frequency of the warehousing areas is
documented.
Areas where are stored returned products, expired drugs,
and drugs in quarantine, are clearly identified. Their access
is limited to authorized individuals.
A system is implemented to ensure an optimal safety of the
quarantine zone.
Temperature is controlled.
All products are warehoused as specified on the labels.
Warehousing areas are sufficiently lighted to favour all
warehousing operations.
Special conditions (temperature, humidity, light, etc)
required for warehousing drug products during transit are
set up. Verifications are performed and all required
documentations are available.
Extremely active or radioactive products, narcotics and all
other hazardous materials or products are warehoused in a
well-delimited area. Safety measures are set up.
1: not compliant 2: weakly compliant 3: ongoing U: undetermined

23. MONITORING OF STORAGE AREA
-Do you have HVAC system to control the temperature/humidity in storage area?
-Did you perform mapping of all storage area in winter and summer?
-Do you have a validated real-time monitoring system?
-Do you sensors monitoring hot & cold spots in your storage area?
-Do all probes and sensors calibrated at least once per year?
•Temperature distribution studies should be carried out on cooled storage areas; the
uniformity of the temperature distribution must be demonstrated.
•The temperature in refrigerators and cold rooms should be continuously measured.
•The data of the temperature recordings should be available and check out regularly.
•Alarms used to monitor the temperatures of storage enclosures should be checked out
regularly.
•Instruments used to supervise and control the temperature of products in stock should
be calibrated at least once a year.

24. MONITORING OF WAREHOUSING AREA
Note:In conformity with the regulations/standardsbelow: USP 1079, General Chapters; USP 1118, General Chapters
Regulation/Standard
Compliance
Recommandations
123U
Analyses of the temperature distribution in warehousing
areas dedicated to temperature sensitive products are
performed. The uniformity of the temperature distribution is
demonstrated (Equipment Qualification).
The temperature (humidity) in the in the warehousing areas
dedicated to temperature sensitive products is continuously
controlled and monitored.
Temperature alarms in the warehousing areas are
periodically verified.
The temperature recording data and alarm reports are
available. Verifications are done periodically at predefined
intervals.
Continuous monitoring sensors are disposed at locations
where temperatures correspond to extreme temperatures as
defined by the temperature recording.
Instruments and devices used to monitor and regulate the
temperature are calibrated at least once a year.
1: not compliant 2: weakly compliant 3: ongoing U: undetermined

25. CONTINUOUS MONITORING
Temperature Monitoring System for Storage and Transportation
Monitor and Track Storage &
Transport Conditions throughout the
Supply Chain, up to the End-users

26. MONITORING OF WAREHOUSING AREA
Monitoring of the Cold Supply Chain
•Global Monitoring / Tracking Solution: ATP-Mirador™ Global
ATP-Mirador™ Global enables you to monitor continuously your Cold Supply Chain.
•ATP-Mirador™ Solution + WirelessxTagSensor Technology
•100% Wireless
•xTagSensors act as relays.
•xTagSensors can work as Data
Loggers.
•Mesh Sensor Network, detects
automatically incoming Sensors.

27. MONITORING OF WAREHOUSING AREA
Monitoring of the Cold Supply Chain
•Global Monitoring / Tracking Solution: ATP-Mirador™ Global
•ATP-Mirador™ Solution + WirelessxTag Technology

28. GLOBAL MONITORING APPLICATIONS
Example of an international supply chain with the ATP-Mirador™global
monitoring solution (combined real-time and continuous modes)

29. MONITORING / DATA LOGGING
Monitoring of the Cold Supply Chain
•Data Loggers and Management System: ATP-ThermoProfile™
Ensure Cold Chain Compliance & Analysis:
•Perform Temperature recording
•Map Storage areas
•Perform Qualification of Storage equipment
•Perform Profile Analysis in Transport
•Monitor Warehousing / Storage areas
•Monitor Products and Shipments
Multiple Data Logger and Thermocouple models are
supported:
•Temperature
•Temperature/R.H.
•Reusable / Single-use
•Pigtail
•Thermoocouples
•USB loggers

30. MONITORING / DATA LOGGING
Monitoring of the Cold Supply Chain
•Data Loggers and Management System: ATP-ThermoProfile™

31. DRUGS TRANSPORTATION
–Did you perform a temperature profile Study in Transport?
–Do you have qualified packaging system for your shipments?
–If not, do you monitor all shipments?
–Do you have a Quality agreement signed by your transport subcontractor?
–What do you do with the shipments of your ambient products?
•The packing used during the transportation of Drugs should ensure the temperature
uniformity in the container.
•Temperature and moisture control equipments should be calibrated regularly.
•If necessary, pest-destroying measures should be applied to containers and vehicles.
•During the transport of Drugs in cold chain, insulating containers should be used, avoiding
direct contacts between Drugs and conditioners, thus preventing the Drugs freezing.
•The means of transport for Drugs requiring a specific storage temperature should be
provided with recorders and temperature sensors able to take acquisitions of temperature all
along the period of transportation.
•Temperature recorded data, for each delivery, should be analyzed. There must be a
procedure to apply corrective actions in case of unfavourable events during transportation.
•Temperature recorded data should be available for any checking.
•Instruments used for the monitoring of temperatures during transportation should
be checked out regularly and calibrated at least once a year.

32. DRUGS TRANSPORTATION
•According to the nature of Drug to transport, adequate precautions should be taken (ex:
control of temperature...).
•Drugs should be transported so that:
–Their identification is clear and available;
–They do not contaminate, and are not contaminated by other products;
–Precautions are taken to avoid any damage and breaking;
–They will not be exposed to conditions likely to deteriorate their therapeutic quality (heat, cold,
light, moisture...).
•During the preparation of a delivery, following information should be taken into account:
–Destination;
–Transportation duration;
–Seasons;
–Nature of Drugs.

33. DRUG PRODUCTS TRANSPORTATION
Note:In conformity with the regulations/standardsbelow: USP 1079, General Chapters; PDA Technical report No39
Regulation/Standard
Compliance
Recommandations
123U
Taking into account the nature of the drug product to be
transported, appropriate cautions are taken.
.
During the transportation of a drug product under cold chain,
warnings (e.g. «perishable drug products» or «do not
freeze») is clearly visible on the container label. This label
is firmly affixed and is water-resistant characters. The
associated documentation clearly mentions that, at
reception, drug products shall be warehoused immediately
and at the indicated temperature.
Drug products are transported in such a way that:
They do not contaminate and are not contaminated by
other products;
Packages and containers avoid any product damages
during the transportation.
They are not exposed to environmental conditions that
could alter their therapeutic qualities (heat, cold, light,
humidity, physical stresses…).
1: not compliant 2: weakly compliant 3: ongoing U: undetermined

34. DRUG PRODUCTS TRANSPORTATION
Note:In conformity with the regulations/standardsbelow: USP 1079, General Chapters; PDA Technical report No39
Regulation/Standard
Compliance
Recommandations
123U
During the drug products transportation under cold chain,
insulated containers are used.
When controlled warehousing conditions* (e.g. temperature,
relative humidity, light) are necessary during transit, required
controlling actions** are taken.
A temperature monitoring system is installed throughout
drug products transportation. The reports of the temperature
recording are controlled and kept in files.
Devices used for temperature and humidity monitoring are
periodically calibrated.
When a shipment under cold chain is prepared, the following
points are taken into consideration:
the destination;
the transportation length of time;
the season;
the type of drug product
1: not compliant 2: weakly compliant 3: ongoing U: undetermined

35. DRUG PRODUCTS TRANSPORTATION
Note:In conformity with the regulations/standardsbelow: USP 1079, General Chapters; PDA Technical report No39
Regulation/Standard
Compliance
Recommandations
123U
The package for the product transportation ensures a uniform
distribution of the temperature in the container, and keeps the
product within the limits of the acceptable temperature range
(Transportation Container Qualification).
Temperature recorders and other monitoring recorders are installed
in the vehicles and refrigerated transportation containers if they
represent the main method for controlling the ambient temperature.
However, these actions are not necessary if a probated (and
qualified) isothermal container is used as the main method for
controlling the ambient temperature.
The following criteria are taken into consideration to select a
container or a transportation box:
Warehousing and transportation requirements ;
Volume required regarding the quantity of product;
Extreme temperatures estimated for the ambient environment;
The estimated duration of the transportation, including any transit warehousing
1: not compliant 2: weakly compliant 3: ongoing U: undetermined

36. DRUG PRODUCTS TRANSPORTATION
Note:In conformity with the regulations/standardsbelow: USP 1079, General Chapters; PDA Technical report No39
Regulation/Standard
Compliance
Recommandations
12 3 U
When warm or cold packs are placed in containers used to
transport temperature sensitive drug*:
The type, size and number of packs correspond to the shipping duration and
temperature needed.
The locations of the packs ensure the product is maintained within the
recommended storage conditions.
Frozen packs are conditioned prior to final packing by allowing them to
“sweat”.
Adequate barrier materials are used to avoid direct contact of the packs with
the products.
When dry ice is placed in containers used to transport
temperature sensitive drugs, in addition to safety issues, it must
be ensured that the dry ice or its vapours does not have an
adverse effect on the drug product or its primary package.
If necessary, antiparasites actions are applied to transportation
containers and vehicles.
1: not compliant 2: weakly compliant 3: ongoing U: undetermined

37. DRUG PRODUCTS TRANSPORTATION
Security (Air Transportation)
•Background
–Provide for screening of all property, cargo, carry-on and checked baggage, and other articles,
that will be carried aboard a passenger aircraft operated by a domestic or foreign air carrier; and
–Establish a system to screen, inspect, or otherwise ensure the security of freight that is to be
transported in all-cargo aircraft as soon as practicable.
•Screening Air Cargo
–Certified Cargo Screening Program (CCSP): A key component of TSA’s response to the 9/11
Act mandate is the Certified Cargo Screening Program (CCSP).
Under CCSP TSA will certify cargo screening facilities located throughout the United States that
screen cargo prior to providing it to airlines for shipment on passenger flights.
Participation in the program is voluntary and designed to enable vetted, validated and certified
supply chain facilities to meet the 100 percent screening requirement.
–Today, multi-layered approach to air cargo security: allowing only known and established shippers
to offer cargo to passenger airlines for shipment, randomly screening a significant percentage of
all cargo, deploying explosive detection canine teams at high volume cargo airports and
conducting covert tests and no-notice inspections of cargo operations by hundreds of inspectors.

38. DRUG PRODUCTS TRANSPORTATION (AIR)
Certified Cargo Screening Program (CCSP)
Screening 100 percent (100%) of cargo on passenger aircraft is designed to ensure the
safety of the traveling public.
TSA designed CCSP to provide businesses with the option to screen cargo in a cost
effective manner and at various points of the supply chain.
CCSP allows businesses to:
–Screen cargo where it is packaged
–Maintain in-house packaging integrity
–Avoid screening log jams at the airport
–Build bulk configurations to minimize cost
CCSP:
–Is supported by the air freight and air carrier industries
–Leverages best practices from global supply chain programs
–Allows businesses to choose the best and most effective model for their needs

39. DRUG PRODUCTS TRANSPORTATION (AIR)
Certified Cargo Screening Program (CCSP)
•Who can be involved ?
–Any facility that tenders cargo directly to an air carrier or indirect air carrier (IAC) may apply
for the Certified Cargo Screening Program. Includes: Manufacturers, Warehouses,
Distribution Centers, Third Party Logistics Providers, Indirect Air Carriers, Airport Cargo
Handlers, Independent Cargo Screening Facilities.
•CCSP Requirements: Certified Cargo Screening Facilities must meet the rigorous
security requirements for their physical location, personnel, and screening.
–Security: CCSP participants must have processes in place to screen prospective
employees and contractors to TSA standards.
Routine reviews of employees with access to cargo after screening must be conducted.
Security threat assessments must be conducted on all employees as described in CCSP
regulatory documents.
Specialized training is also required for all person who will conduct screening, handle cargo,
or have access to designated screening areas.
–Screening: CCSP participants must have procedures in place to prevent unauthorized
access to cargo facilities where cargo is screened, prepared, or stored.
Physical barriers must be in place at cargo handling and storage facilities as well as
designated screening areas.

40. DRUG PRODUCTS TRANSPORTATION (AIR)
Certified Cargo Screening Program (CCSP)
Chain of Custody: Supply chain participants are required to maintain chain of custody
standards for screened cargo. The standards must include all of the following:
–Documentation: Information must be documented and included with the shipment
–Methods-must be employed to ensure the cargo is secure and maintained throughout the
shipping process
–Authentication-documentation and methods must be authenticated upon receipt by each
party and at each point in the supply chain.
Key Considerations: Each business should carefully examine the options and
determine which method of screening program is right for their entity. Some factors to
consider:
–Are your shipments carried on passenger aircraft?
–Will your shipments be comprised if opened for screening?
–What will screening cost?
–Are you products sensitive to shipping delays?
–Are you participating in other supply chain programs? (C-TPAT, cGMP, TAPA or other)
–Does the amount of shipping justify in-house screening?

41. DRUG PRODUCTS TRANSPORTATION
PACKAGING
Packaging for Drug products
–Must fulfill the users’ specifications requirements
–Must be designed thermally
–Must be related to Temperature Profile(s)/Logistic history
–Must be qualified thermally
–Must be verified
–Must be maintained (periodic control)
Standards/guidelines:
–ISTA (5B, 7D, 7E, Standard 20)
–PDA Technical Report No39, revised 27

42. DRUG PRODUCTS TRANSPORTATION
PACKAGING
ISTA 7E & Standard 20:
•New ISTA 7E Profile:
–Based on 83 routes, on 12 months
–From Louisville, KY, star pattern distribution scheme,
destinations close to known pharmaceutical
distribution hubs were chosen.
–The profile is not intended to be geographically-specific,
these profiles have global applicability.
–The ISTA 7E profiles have been developed by mapping
the temperatures experienced in the 'shipping lanes' and
not the temperature a particular geography was
experiencing during those months.
–Experts in thermal shipping have agreed that these
profiles encompass perhaps well over 90% of the
shipping thermal challenge encountered in all seasons.

43. DRUG PRODUCTS TRANSPORTATION
PACKAGING
ISTA 7E & Standard 20:
•Standard 20
–Standard 20 is a design and qualification process for
insulated shipping containers.
It is a comprehensive set of requirements to achieve
a certified package according to ISTA 7E.
–ISTA Standard 20 Certification: for Labs
Audited by certified ISTA auditor
Provides Certified Thermal Professional
•ISTA 7E Certification Mark for Package
–A certified package signified that the shipper has
been qualified to all the requirements of ISTA 7E.
–The documentation is complete for any purpose since
the testing is comprehensive. Users with internal SOP's
calling for further testing can follow those, but no further
testing isrequired to comply with Standard 20.
–Users with known exceptions can perform field testing to
determine which Certified shippers are appropriate in those instances.

44. DRUG PRODUCTS TRANSPORTATION
PACKAGING
ISTA 7E & Standard 20:
•ISTA Standard 20 Process
–Step 1.ISTA Standard 20 is purchased from ISTA.
–Step 2.Standard 20 Laboratory Certification application is
submitted to ISTA.
–Step 3.1-2 key laboratory personnel become certified thermal
professionals level I and II.
–Step 4.Laboratory is audited and approved by ISTA Certified
Auditors.
–Step 5.ISC is tested in accordance to ISTA Standard 20.
–Step 6.ISC testing results and documentation submitted to
ISTA.
–Step 7.ISTA review results and issue Standard 20
certification mark for ISC.

45. FOLLOW-UP
Following the Regulatory Gap Analysis, a Cold Chain
Compliance program can be established:
•Staff members
•Documentation
•SOPs
•Reception area
•Storage area
•Monitoring of storage area
•Transportation of drug products
•Monitoring of temperature in transport
•Returned products
•Returned of non defective products
•Emergency plan/drug products recall
•Quality agreements

46. RECOMMENDATIONS
•Regarding to the existing processes and regulatory requirements, it is usually
recommended to implement:
–Training: Training session to management, employees and all staff who
manipulates sensitive products.
–Documentation: The Company must have documents attesting that drug
(refrigerated and ambient) warehousing conditions comply with regulatory
requirements in term of external conditions like temperature, but also handling and
transportation.
–SOPs: The Company shall revise its SOP, and complete them, notably for its
narcotics, and its thermal equipments.
–Mapping & Qualification: The Company must realize or complete the mapping and
qualification of its warehouses, vaults, fridges, freezers, walk-in, to determine
temperature distribution and to store its products in a manner to not affect their
characteristics.
–Monitoring: Temperature and humidity have to be controlled, and data must be
available every time with a real time monitoring system.
This system has to be fully compliant, with alarms management, audit trail and
reports management for identified persons only. All data have to be filed in
a secure system and be easily available for legal requests.

47. RECOMMENDATIONS
Cont’d
•Regarding to the existing processes and regulatory requirements, it is usually
recommended to implement:
–Temperature Profile: The Company shall determine the temperature distribution
profiles that apply onto its sensitive products along all the distribution and
transportation processes during warm and cold weather conditions.
–Qualified Packaging Methods: The Company shall design and use insulated
containers, conditioning materials and methods for shipments and storage, that are
proven to maintain an internal temperature compliant with products labelling, during
all transportation or storage process (including receiving) until product is packed-out
and stored in the range of temperature applied.
Such packaging and shipping methods shall be consistent with the distribution
conditions and shall be qualified.
–Quality agreement: Agreement have to be signed with subcontractors.

48. CONCLUSION
Performing an efficient Cold Chain Regulatory Compliance and Gap Analysis is a crucial
step for a continuous improvement of Cold Chain Compliance. A special attention should be
put on:
•Personnel Training, Documentation, Records and SOPs: Comply with CFR 205, CFR 211 and
USP Chapter <1079>
−Train your staff and personnel about Cold Chain aspects and SOPs; Documentation and
SOPs on Cold Chain processes
•Mapping and Qualification: Comply with USP Chapter <1079>
−On all Storage areas.
•Changes in Storage Conditions: Comply with CFR 211
−In Warehouses and Equipments (Change Control).
•Monitoring: Comply withUSP Chapter <1079>, <1118>
−Ensure an efficient Monitoring of your Storage areas and Transports.
•Temperature Profile and Qualified Packaging Methods:Comply with PDA Technical Report
No39, ISTA 7E and Standard 20
−To be installed and periodically controlled and updated (Cold Chain Maintenance).
•New Regulations:
−Be aware about new regulations and constraints during Transports (Air, Ground, Sea): TSA
•Quality Agreements: Comply with USP Chapter <1079>
−To make sure that all parties will manipulate, store and transport Products according
to their sensitivities.

49. Express Survey
According to you and from your actual
knowledge, how do you evaluate your level of
compliance on the different regulations on Cold
Chain management?