Develop an Effective Protocol for Conducting Transportation Studies … 12... · Develop an Effective Protocol for Conducting Transportation Studies 12/8-10/15 1. 2 References ...

Karem Y. Monge SepúlvedaMS Physics, CQA

Senior Scientist-Technical ServicesMylan LLC

Develop an Effective Protocol for Conducting Transportation Studies

12/8-10/151

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References– PDA TR 39 Guidance for Temperature – Controlled Medicinal Products:

Maintaining the Quality of Temperature-Sensitive Medicinal Products Through the Transportation Environment (Revised 2007)

– PDA TR 64 Active Temperature-Controlled Systems: Qualification Guidance

– FDA Guidance for Industry: Stability Testing of Drug Substances and Drug Products (Draft 1998)

– US FDA 21 CFR Part 11, 210 & 211, and 820

– WHO TR No. 953, 2009 Annex 2: Stability Testing of Active Pharmaceutical Ingredients and Finished Pharmaceutical Products

– WHO TR No. 863, 1996 Annex 5: Guidelines for Stability Testing for Pharmaceutical Products Containing Well Established Drug Substances in Conventional Dosage Forms

– EU Guidance on Good Distribution Practice of Medicinal Product for Human Use

– Guide 0069 Health Canada’s Guidelines for Temperature Control of Drug Products during Storage and Transportation

– ICH Q1A (R2) Stability Testing of New Drug Substances and Products (2 February 2003)

– USP <1079> Good Storage and Shipping Practices

General Information

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› What is “Cold Chain”?– The term “cold chain” or “cold chain management” refers to

controlled temperature transportation of pharmaceutical products, biologicals, and active ingredients.

– It applies to:

› diagnostics, research, and investigational materials that require temperature control.

› refrigerated and frozen products (i.e. cold chain products)

– in general, they are products which have storage temperatures cooler than Controlled Room Temperature (CRT) or are very sensitive to temperature variation, on both sides of the storage range.

› Cold chain and Cold Chain Management are often used interchangeably.

What is a Cold Chain Process (Transportation of Product)?

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Some medicinal products require storage under controlled temperaturein order to maintain product quality. In addition to those labeled forrefrigerator or freezer storage, some products are stable at controlledroom temperature but may suffer degradation at temperature of 30°C orabove or at temperature below 0°C due to freezing.

› What is the Goal?– Keep the “temperature sensitive” product within the designated

temperature range to ensure that product quality, safety, efficacy, and stability is maintained.

– Comply with regulations– Minimize cost– Increase efficiency

› Why?– Rapid growth of biopharmaceuticals in addition to complex

distribution chains with a variety of transportation modes (i.e. Global sourcing and distribution).

– Business Impact (i.e. high value of products, long lead times and limited supply, company reputation).

– Increased scrutiny of product protection during transport

Why is it necessary?

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› It applies to:– any pharmaceutical product, biological, active ingredient, devices,

and combination products.

– diagnostics, research, and investigational materials that require temperature control

– animal products

– finished products (unlabeled bulk drug product, labeled drug, finished packaged kits)

– process intermediates (i.e. column eluates)

– samples (for GMP testing)

– reference standards.

To What Does Cold Chain Management Applies?

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› ICH Q1(R2) – Section 2.2.7 Storage ConditionsA drug product should be evaluated under storage conditions (w/

appropriate tolerances) that test its thermal stability, and ifapplicable, its sensitivity to moisture or potential for solvent loss.

The storage conditions and the lengths of studies chosen should besufficient to cover storage, shipment, and subsequent use.

Data from accelerated storage conditions and, if appropriate, fromthe intermediate storage conditions can be used to evaluate theeffect of short-term excursions outside the label storage conditions(such as might occur during shipping).

Acts, Rules, and Regulations for Cold Chain Management?

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› Who Annex 5 - Definitions

… The data thus obtained, in addition to those derived from real-timestability studies, may be used to assess longer term chemical effectsunder non-accelerated conditions and to evaluate the impact of short-term excursions outside the label storage conditions, as might occurduring shipping…

› FDA, CFR 21 Part 203.32

States that manufacturers, authorized distributors of drugs and theirrepresentatives should store and handle all drug samples underconditions that maintains their stability, integrity, and effectiveness andensure that the drug samples are free of contamination, deteriorationand adulteration.


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› EU Guidance (94/C63/03)

“The Quality System operated by Distributors (wholesalers) ofmedicinal products should ensure that storage conditions areobserved at all times, including during transportation…

…Medicinal products requiring controlled temperature storage shouldalso be transported by appropriate specialized means...


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› FDA has the authority to regulate transportation of products:– 21 CFR 211.150 – addresses distributions procedures

– 21 CFR sections 203 and 205 – good practices for holding products

– NDA/ANDA labeling requirements

– Application and GMP requirements regarding stability (21 CFR section X) and expirations dates (21 CFR section X).

– USP Monographs, general notices and information chapters

› USP General Chapter <1079> - Good Storage and Shipping Practices

› USP General Chapter <1118> - Monitoring Devises – Time, Temperature and Humidity

› USP General Chapter <1150> - Pharmaceutical Stability


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› Regulatory Trends and Expectations:– In recent years, global regulatory agencies have increased oversight

to ensure the integrity of pharmaceutical products in the distribution chain.1

– Trends

Responsibility for cold chain management ultimately resides with the manufacturer.

Manufacturers are expected to thoroughly understand the stability profile of their products and maintain the necessary controls during the distribution process.


111. Cold Chain Management-An Essential Component of the Global Pharmaceutical Supply Chain, R. H. Bishara(2006-American Pharmaceutical Review)

› Regulatory Trends and Expectations (Cont’d):

– Trends (cont’d)Increased importance of temperature control and monitoring to

mitigate and identify risks during cold chain transport.

Over 36% of all critical and major deficiencies of RegulatoryCitations are related to: monitoring devices and theirlocations, temp monitoring records, shipping containers,controlled use of cooling elements, uncertain audit trail,trailer’s temp mapping, contract transport and audit.

Other issues are: training of warehouse personnel, drivers,etc., calibration of temp monitoring devices, maintenance ofthe cold chain of imports, and maintenance of the cold chainto the patient level.


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– Trends (Cont’d)Heightened priority of Patient Safety.

SOPs and records for shipping and receiving are available andcontain the following:

• Shipping configuration and type of protective packaging

• Labeling requirements (storage conditions, specialinstructions or warnings for shipment)

• Mode(s) of transportation approved for shipping

• How shipments of the finished product are to be sealed

• Verifications required to ensure that no finished product onthe shipment has been tampered with and that there areno damaged containers

• Evidence that shipping requirements (e.g. temperaturecontrol) have been met.


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– Expectations

Stability studies to support temperature excursions

Qualification (Verification) for seasonal shipping configurations and load size

Monitoring of shipping temperatures to ensure product quality


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Transportation Study

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› Why prepare your study to minimize temperatureexcursions?– Knowing the distribution variability helps in the performance of a

gap analysis on the distribution environment.

› This minimizes product loss and business impact.

– The longer the product is stored at uncontrolled conditions, thegreater the risk to the product.

› Thus, in order to mitigate the risk, manufacturers need tounderstand every aspect of the distribution chain.

– Evaluate data from long-term and accelerated stability studies,temperature excursion studies and/or temperature cycling topredict the impact of temperature excursions on product qualityduring transportation process.

– Understand the responsibilities of shipper, receiver, andmanufacturing site to quickly communicate excursions for resolutionas quickly as possible.

Pre-requisites and Requirements for a Shipping Study

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› Considerations for a Shipping Study– Customs

– Hemispheric, climatic, and seasonal variations

– Mode of Transportation and Route

– Identify Product

– Stability Data and any other studies conducted for productrobustness

– Temperature Sensitivity

– Quantity of temperature monitoring devices needed and time range


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› Considerations in the Selection of Shipping Route– Hemispheric, climatic, and seasonal variations

– Temperature of shipping method

– Mode of Transportation and Route

– Length and variability of shipment time needs to be understood andestablished (duration)

– Vibration effects on material / product being shipped

– Effects on containers and venting (air pressure cycles)

– Physical Stresses – crushing, handling, dropping, leakagefrom/onto, package orientation, package placement

– Security – inspection, tampering, radiation exposure


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› Considerations in the protection of the product duringtransportation– Temperature controlled trucks and trailers for ground transportation

– Temperature controlled ocean containers

– Active Systems (Shippers) temperature control for air transport (i.e.envirotainers)

– Passive Systems (Shippers) temperature control for all modes oftransportation – qualified protective packaging such as a D-Container


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› Generally speaking, the supply chain cannot be “validated”;however the principles of validation can be used to qualifyportions of the supply chain.

Principles of Validation

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Critical Components of Qualification› Component Qualification

– Establishes confidence that ancillary component systems arecapable of consistently operating within established limits andtolerances.› additional means used in combination with the basic transportation unit

maintain the required temp during transport

– Critical components are those with quality parameters that mayreasonably be expected to affect the acceptance criteria of a coldchain shipment (temp monitors, insulated shipping containers,refrigerants such as a gel pack.

– Most commonly included in the DQ and OQ.

Process to Qualify Protective Packaging

› Functional Requirements– Summarizes the critical parameters required to initiate the cold chain

process. The purpose is to document the critical parameters of theproduct, packaging, and transport system already identified.

– Critical parameters include:› Shipping Distribution or Transportation (duration, mode, route, climatic

conditions)› Product stability (temperature range) – used to define the limit of time,

temperature and humidity in which the product is stable during storage› Packaging (primary, secondary, and market package)› Minimum and maximum expected shipping volume› Minimum and maximum thermal mass (this is the assembly of primary

and/or secondary packaging with tertiary packaging components in theform of the basic transportation as the overall thermal mass that mustbe temperature-controlled)

› Expected ambient profiles› Material requirement and restrictions› Marketing requirements› User requirements

Critical Components of Qualification

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› Design Qualification (DQ)– The purpose is to ensure that the Functional Requirements is met

by the proposed package or system.

– Typically includes:

› Process duration

› A defined ambient temperature profile

› Quantity, temperature condition, and location of refrigerant or airconditioning system

› Product shipping configuration with the temperature monitoringdevice location

› Type of insulated material / air conditioning system

› Minimum and maximum thermal mass and loads

› Location of temperature monitoring device location.


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› Operational Qualification (OQ) and Performance Qualification (PQ)

– Should be performed using designated transport configuration toprovide assurance that product quality is maintained duringtransport.

– OQ reflects transportation qualification tests conducted in a temp-controlled chamber or other simulated test conditions.› It should use a temp/cycle that contains the anticipated extremes in time and

temperature for the transportation of the drug product.

› Typically includes:

– Exposure to temperature that encompass the anticipated extremes inambient temperatures customary in shipping/distribution over theroute/region and in the temperature/season(s) being qualified.

– Testing done using the same packaging configuration (pack-out) finalizedin the development phase or rationale provided if using other.

– Testing repeated a minimum of three (3) times, using three (3) samplecontainers with components, at each set of conditions (load minimum andmaximum or worst-case) and tem cycle (hot and cold or worst-case) isnecessary.


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› Operational Qualification (OQ) and Performance Qualification (PQ)

– PQ consists of consecutive, replicate field transportation tests todemonstrate that the process is effective and reproducible.

– Typically includes:

› Use of actual drug product or placebo

› Actual ambient temperature variances, including seasonal changes

› Representative load configurations

› Defined packing configurations

› Calibrated temperature monitoring devices

› A sufficient number of tests to assure reliable results.

– At least one primary calibrated temp monitor and one backupmonitor included in each shipping container (inside container temp)and one primary and one secondary monitor on the outside of eachshipping container (ambient outside temp).

› Protocol must adequately describe the packaging and shippingprocesses that will be utilized for commercial shipments

› Routes, modes, seasons, and times representative of commercialshipping conditions


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› Process Implementation and Training– The specific transport system and temp controlled packaging

systems are confirmed during qualification.

– Transfer of the qualified process to the operational area is formallyaccomplished by means of approved procedures that will implementthe controls of critical process parameters, which will result inrepeatable, successful transport of medicinal product.

– Training should provide instruction to relevant personnel andorganizations participating in the temp controlled processconcerning the principles of packaging, qualifying, and transportingtemp sensitive medicinal product.


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› Process Implementation and Training (Cont’d)– The shipping or receiving area shall be responsible for reviewing

temp monitor data, when monitors are included in shippingcontainers, and may approve shipments based on these data whenthere are no deviations.

– There shall be procedures for implementing corrective actions in thecase of deviations. The QU, with an evaluation by TechnicalServices, shall be responsible for making accept/reject decisions forshipments w/deviations.

– Change Control

› Quality agreements w/suppliers of cold chain components mustcontain wording, which requires that suppliers inform the Site ofany changes in materials, the manufacturing process,specifications or changes of significance.


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› Monitoring– In order to maintain the process in a state of control, process

parameters shall be monitored and trended when sufficient data areavailable.

– Example of methods and data that may be used include:

› Analysis of data from temp monitoring devices used in shipments.

› Analysis of customer complaints/return type and frequency data.

› Analysis of data from temp monitoring devices used periodicallyin distribution of products to customers.

› Analysis of weather data obtained either from historicalrepositories or from shipments designed to measure shippingroute ambient temps.


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› Why perform Stability Studies?1

– The purpose of Stability testing is to provide evidence of how thequality of an API or FPP varies with time under the influence of avariety of environmental factors such as temperature, humidity andlight, as well as to establish a retest period for the drug substanceor a shelf life for the drug product and recommended storageconditions.

– The choice of test conditions is based on an analysis of the effectsof climatic conditions in the three regions of the EC, Japan and theUnited States.

– In general, a drug substance should be evaluated under storageconditions (with appropriate tolerances) that test its thermal stabilityand, if applicable, its sensitivity to moisture. The storage conditionsand the lengths of studies chosen should be sufficient to coverstorage, shipment, and subsequent use.

The Importance of Stability

281. ICH Q1A (R2) and WHO Annex 2

› Why perform Stability Studies?1

– The stability program also includes the study of product-relatedfactors that influence its quality, for example, interaction of API withexcipients, container closure systems and packaging materials. Infixed-dose combination FPPs (FDCs) the interaction between two ormore APIs also has to be considered.



Study Storage Condition Minimum Time Period Covered by Data at

Submission

Long-term1 25°C±2°C / 60%RH±5%RHor

30°C±2°C / 65%RH±5%RH

12 months

Intermediate2 30°C±2°C / 65%RH±5%RH 6 months

Accelerated 40°C±2°C / 75%RH±5%RH 6 months

1. It is up to the applicant to decide whether long term stability studies are performed at 25 ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH.

2. If 30°C ± 2°C/65% RH ± 5% RH is the long-term condition, there is no intermediate condition.

› Storage Conditions– Refrigerator Storage Statement (per USP)

› The storage statement for labeling may be: “Store in a refrigerator, 2°C to 8°C (36°F to 46°F)”.



Study1 Storage Condition Minimum Time Period Covered by Data at

Submission

Long-term 5°C±3°C 12 months

Accelerated 25°C±2°C / 60%RH±5%RH 6 months

› Storage Conditions– Freezer Storage Statement (per USP)

› The storage statement for labelling may be: “Store in a freezer, --25°C to -10°C (-13°F to 14°F).



Study1 Storage Condition Minimum Time Period Covered by data at

Submission

Long-term -20°C±5°C 12 months

› Storage Conditions– Controlled Cold Temperature

› Involves Mean Kinetic Temperature (MKT) Formula

› 2°C to 8°C, with excursions allowed down to 0°C and up to 15°C during storage, as long as MKT does not exceed 8°C.

› Transient spikes of up to 25°C are permitted for no more than 24 hours, unless there is additional supporting data.



– The choice of test conditions are to be defined on an analysis of theeffects of climatic conditions.

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Climatic Zone DefinitionStorage

Conditions ºC

Countries1, 2

ITemperate Climate (Cold winter, mild

summer)21 / 45

Quebec-Canada, Japan, USA, Buenos Aires-Argentina, Amsterdam-Netherlands, London-England, Seoul-Korea,

Incheon-Korea, Russia, Switzerland, Ukraine, China

II

Sub-tropical and Mediterranean

climates(Semiarid, Mediterranean, Marine

W. Coast, Humid Subtropical, Tundra,

Highlands)

25 / 60

Miami-USA, New York-USA, Atlanta Georgia-USA, Santiago-Chile, Nablus-Palestine, Rome-Italy, Milan-Italy,

Catania-Italy, Mexico, Peru, (Tel Aviv Yafo) Israel, Uruguay, Bolivia, Afghanistan, Iran, Egypt, Algeria, EU, Algeria, Morocco, Namibia, South Africa, China, Sydney-

Australia

III Hot, Dry climate (Arid) 30 /35Iraq, Amman-Jordan, Karachi-Pakistan, Saudi Arabia3,

United Arab Emirates, Qatar, Kuwait, India

IVa Tropical Dry 30 / 65

Barbados, Belize, Brazil, Costa Rica, Dominican Republic, Ecuador, PR, El Salvador, Guatemala, Guyana, Haiti,

Honduras, Jamaica, Colombia, Cuba, Nicaragua, Dutch Antilles, Panama, Paraguay, Puerto Rico, Venezuela, Hong Kong, Bangkok-Thailand, Jakarta4 - Indonesia, Bangladesh, Manila-Philippines, Singapore, Taiwan,

Taipei-Taiwan, Kuala Lumpur-Malaysia, Saigon-Vietnam, Colombo-Sri Lanka, Madagascar

IVb Tropical Wet 30 / 75

– The choice of test conditions are to be defined on an analysis of theeffects of climatic conditions. (Cont’d)

1. ICH Q1A(R2) Guideline – Countries assigned to the climatic zones I and II

2. ICH Q1F Guideline – Countries assigned to the climatic zones III and IV

3. Saudi Arabia is one of the driest countries in the world. Temp can reach 55ºCin some areas in summer time(www.wordtravels.com/travelguide/countries/Saudi+Arabia/climate)

4. Jakarta is one of the hottest and most humid capitals in the world(www.worldexecutive.com/cityguides/jakarta/weather.shtml) 34

Criteria1,2 Guide values for individual climatic zone

I II III IV

Mean Annual Temp measured in open air (oC)

Up to 15 > 15 - 22 > 22 > 22

Calculated mean annual temp (oC) Up to 20.5 > 20.5 - 24 > 24 > 24

Mean Annual water vapour partial pressure (mbar)

Up to 11 > 11 - 18 Up to 15 > 15

http://www.wordtravels.com/travelguide/countries/Saudi+Arabia/climate

– The choice of test conditions are to be defined on an analysis of theeffects of climatic conditions. (Cont’d)

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MonthsSeasons

North Hemisphere South Hemisphere

September - November Fall (F) Spring (Sp)

December - February Winter (W) Summer (S)

March - May Spring (Sp) Fall (F)

June - AugustSummer (S) Winter (W)

› Why perform thermal (time/temp) cycling studies?– To know behavior of product at the extremes, define the limit of

time, temp, and humidity in which the drug product is stable duringstorage.

– Chemical profile of product exposed at temperature extremes as aprojection through time and considering the Stability Program.

– Studies to support short-term temperature excursions on thestability profile of the product.

› Temperature stress studies for a period of time at a certaintemperature. Then, samples are placed in Accelerated Storage(ACC – 40°C±2°C / 75%±5%RH) conditions in the StabilityProgram.


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› Data Loggers– Programmable temperature and humidity monitors to track and

collect data about temperature sensitive shipments, usually NIST®

traceable and single use.

Examples of Containers and Use of Data Loggers

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Sensitech TempTale4 Marathon Products c\temp data Logger

› Containers– Air Cargo

– Ocean Freight - insulated container

– Envirotainer - thermostat controlled heat exchanger powered by batteries and using dry ice as coolant.


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Air cargo cartons (D-Container type)

Ocean Freight container (ULD type)

Envirotainer (RKN t2 type)

› Active Systems (Shippers)– Systems with active temperature control (e.g. air freight container,

refrigerated trucks/cars).

– System that uses a thermostat-controlled container that usually employs fans and dry ice as refrigerant and is powered electronically


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› Passive Systems (Shipper)– Systems without active temperature control (e.g. insulated

containers with or without refrigerants)

– Typically consists of a box with gel-packs, freezer-packs or dry ice within an insulated box

– Often sold as pre-qualified stock items by commercial vendors


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› When making the choice between active an passive systems, knowledge of the product and chosen distribution model well have an impact, as well as value of the product and cost of replacement, routes, and necessary thermal protection.1

› Active Systems– The use of active systems provides benefits of high thermal stability,

which can be tailored to the exact temperature range required.

– They can be used under service level and quality agreements, including operational qualification and periodic thermal mapping, availability and suitability.

– However, they are only available in large volumes, and partial loads incur similar costs to full loads.

– The systems are high cost and unless there is a full load, the efficiency of use may be restricted.

Choose: Active or Passive Systems?

421. Temperature-Controlled Packaging Systems: Active or Passive? A. Roskoss (Innovations on Pharmaceutical Technology Issue 37, 2011)

› Passive Systems– The use allows the shipment size to determine the solution used, from

single doses to multiple doses.

– The systems comprise the payload material surrounded by thermal media, which is prepared to specific temperatures and encapsulated within an insulation material.

› This basic construction allows for systems to be shipped without significanthandling restrictions, providing more potential carriers and routes to becomeavailable for the shipment.

– The systems, in comparison with active systems, have considerably lower capital cost and can be stock-held to provide volume flexibility in terms of supply.

– The main use of passive systems is, however, in the maintenance of refrigerated products between +2°C and +8°C.

Choose: Active or Passive Systems?

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Documentation

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› The general purpose of all technical writing is to inform the reader as efficiently as possible.

› The aim of all technical writing is to transfer information.

How to Write an Effective Protocol?

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› Write for the reader– Means identifying who the audience for your document is and what

the purpose of your document is

› Write clear concise English– Means creating clear concise sentences that are easy to read and

understand

– Structure the document in a logical order

› Select relevant appropriate details– Means to focus on the essentials

› Make writing process effective– Means to follow essential rules and guidelines in a systematic way

and maintain the focus on these every time a technical document is written


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› Technical Writing is a 4-phase process:

– Requirements: audience, purpose

› Clarify the audience and purpose (who are we writing for and what we are trying to achieve)

– Design: organization and structure

› Define the structure that our document will have and organize the information accordingly

– Implementation: draft

› Write the draft

– Testing: revision

› Review the draft; first by the writer, then it is distributed for a more formal review


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› Audience (Write for the reader)

– Before writing anything, define clearly:› Primary Audience: who, what, when, how

– Who is the main person or main group who will read and use this document?

– Who will perform?

› Secondary Audience: who else will read it

› Level of knowledge: about this specific subject

– Key question: Do they know about X, Or have they done Y before?

– NOTE: The sign-offs are not the Primary Audience, they are the Secondary Reader.

– NOTE: The Auditor is not the Primary Reader / Audience. What they have is a level of knowledge. Thus, no matter time, the document should read effortlessly.


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› Specific Purpose (Write for the reader)

– The specific question for each document: › What is this document meant to achieve? It is a tool to do a job,

where you must define exactly what that job is.

› What difference will it make? The document must make a difference.

› What the reader will be able to do? This is the key question for instructional material like procedures and work instructions and protocols and operator’s manuals.

› What the reader understand? This is the key question for technical reports.

› What action or response do I want? This is a key question for proposals and or technical correspondence.


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› Structure (Write Clear Concise English)

– Do’s and Don’ts:

› Do make it brief (1 or 2 sentences).

› Do take time to be precise.

› Do stick to facts known at the time.

› Don’t be vague.

› Don’t include opinions.

› Don’t include assumptions.

› Don’t give too much or too little information.


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› Clear Concise English “The Golden Rule”

– Sentences

› Short sentences – avoid long sentences

› Avoid complicated constructions

› Keep to 1 or 2 ideas

› Average of 15 to 20 words or less

› Break up long sentences

› Ex. The test cycle was restarted because two units were contaminate. (10 – one idea)

› Ex. The Operations Department compiles inventory forecasts on Friday and issues them to suppliers on Monday. (15 – two ideas/use of clauses)

› Caution:

– Do not write telegraphese (like text messaging)

– Do not omit words

– Do not abbreviate normal words


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› Clear Concise English “The Golden Rule” Cont’d– Paragraphs

› The basic building block

› A set of related sentences

› Divide your subject into topics

› Cover each topic in one paragraph

› Keep paragraphs short

› Aim for a maximum of 5 sentences

› Aim for a maximum of 10 lines.

– NOTE: The main point is to be clear about what the role of the paragraph is – then the correct use of the paragraph will happen naturally.


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› Clear Concise English “The Golden Rule” Cont’d– Verbs

› Tenses: past – present – future

– Past: we observed the reaction (this is after the execution)

– Present: we observe the reaction (used mostly for instructions)

– Future: we will observe the reaction

– Keep the framework of tenses consistent

› Active and Passive

– Active – subject performs the action expressed in the verb

– Passive – subject receives the action expressed in the verb or action is performed on the subject of the sentence


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› Verbs

– In Instructions:

› Use Present Tense for instructions

› Pretend everything happens in the Present Tense

› Also, describe processes in Present Tense

› Use the Imperative, if possible

› Place the Imperative at the start of the instruction, if possible

› Verbs– In Reports:

› Use Passive Voice to report actions and results

› Use the Past Tense to report actions and results

› Optionally, use the Present Tense for discussion, conclusions, and recommendations

› Above all, BE CONSISTENT

How to Write an Effective Protocol?Clear Concise English “The Golden Rule” Cont’d

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› Clear Concise English “The Golden Rule” Cont’d– Lean Writing – (Select Relevant Appropriate Details)

› Three rules:

– Omit needless words

– Omit irrelevant information (not relevant to the purpose of the document

– Omit unnecessary repetition

› Technical Jargon

– Only use jargon that the audience understands

– Explain any word that the audience does not understand

– Use footnotes or a glossary

– Use the words consistently

› Abbreviations

– Are convenient for the reader, not the writer

– Avoid abbreviating ordinary words

– Universally understood abbreviations are acceptable

– Expand abbreviations the first time they occur


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› Draft and Revision– Review your own draft

› Review the Draft thoroughly before distribution

› Take a break between finishing the draft and starting your review

› Try to see the document as your reader would see it

› Get someone else to review it, if possible (peer reviewing)

› “print it out, put it aside, revise with fresh eyes”

– Review someone else’s draft

› Make two careful passes to ensure:

– The document does what it is meant to do.

– The mechanics of the document are correct.

– Suggestions for reviewers› Be constructive ●Adopt a standard dictionary

› Explain what the problem is ● Adopt a style guide

› Suggest alternatives, if possible ●Avoid red ink for markup

› Be consistent

› Provide templates and Guidelines

› Provide a library of model documents


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› Content of the Protocol– Overview

› Special page that serves as a binding contract between the site and end receiver to document any special instructions needed for the shipment

– Introduction

– Purpose

– Responsibilities› Both parties, Site and end receiver, must be included and the Carrier, if needed

– Acceptance Criteria

– Procedure› Request to the Carrier two routes for air shipments, the main route and an

alternative.

– Report

– References

– Attachments for execution

How to Write a Shipping Study Protocol?

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How to Analyze Data?

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› Confirmation, with photos, that shipment arrived in goodorder (visual inspection).

› Confirmation that all temp monitoring devices used werefound within the shipment.– It must comply with any acceptance criteria of maximum quantity

of devices available per pallet.

› Data received must be tabulated.

› Once tabulated, it is evaluated against the acceptancecriteria (temp profile) and any permitted temp excursions.

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Handling Unit and/or

LD9 Number

TempTale Serial

Number

Lowest Temperature Recorded

(ºC)

Highest Temperature Recorded

(ºC)

Time IntervalBelow

+15ºCa

Time Interval Above

+30ºCa

Average Temperature Recorded

(ºC)

Standard Deviation

(ºC)

Mean Kinetic

Temperature (ºC)

402356150 3446924849 +15.5 +24.4 none none +18.7 ±1.6 +18.9

402356151 3446924832 +14.0 +31.5 03:45:00 01:07:30 +19.0 ±2.0 +19.2

402356274 3446924840 +16.1 +24.3 none none +18.7 ±1.3 +18.8

402356520 3446924880 +15.4 +58.5 none none +19.1 ±2.0 +19.3

402356523 3446924893 +12.6 +34.8 16:52:30 01:30:00 +18.7 ±2.7 +19.2

402357145 3446924815 +16.3 +24.2 none none +18.3 ±1.5 +18.5

402355675 3446924885 +17.1 +21.9 none none +18.1 ±1.1 +18.2

402358030 3446924827 +16.3 +23.0 none none +18.0 ±1.3 +18.1

402358089 3446924812 +16.3 +23.8 none none +18.6 ±1.3 +18.7

402357987 3446924813 +12.1 +31.9 21:22:30 01:07:30 +18.4 ±2.5 +18.8

402357988 3446924845 +15.6 +27.6 none none +18.8 ±1.7 +19.0

402357994 3446924884 +15.2 +24.7 none none +19.0 ±1.8 +19.2

402358454 3446924887 +15.9 +31.7 none 01:07:30 +18.7 ±2.1 +19.0

402358458 3446924899 +16.9 +26.4 none none +18.8 ±1.5 +19.0

402358489 3446924859+9.3 +36.1

1 day, 03:00:00

01:52:30 +18.4 ±2.9 +19.0

402354781 3446923278 +13.2 +27.1 07:07:30 none +18.4 ±2.0 +18.6

402354782 3446922267 +12.8 +26.4 09:22:30 none +18.6 ±2.0 +18.9

402355125 3446922293 +12.4 +41.7 17:37:30 03:22:30 +18.3 ±2.7 +18.9

402355131 3446921987 +11.8 +26.7 16:07:30 none +18.0 ±2.3 +18.3

402355138 3446923119 +10.6 +28.4 21:45:00 none +18.3 ±2.4 +18.6

402355488 3446923047 +12.8 +26.6 09:22:30 none +18.3 ±2.0 +18.5

402355569 3446923253 +12.6 +27.3 09:22:30 none +18.5 ±2.0 +18.8

402355878 3446923386 +11.4 +26.7 09:52:30 none +18.4 ±2.2 +18.7

402355782 3446923787 +13.6 +26.4 07:52:30 none +18.8 ±2.0 +19.1

402356056 3446923381 +9.8 +42.31 day,

09:22:3002:37:30 +18.7 ±3.1 +19.3

402356691 3446923323 +13.1 +27.0 06:45:00 none +19.0 ±2.0 +19.3

402355696 3446921975 +12.2 +26.8 06:22:30 none +18.6 ±1.8 +18.8

402357030 3446923351 +12.6 +28.9 11:37:30 none +19.2 ±2.1 +19.4

402357031 3446921979 +12.9 +30.0 07:30:00 none +18.6 ±2.1 +18.9

402357032 3446923116 +9.9 +46.1 20:37:30 03:00:00 +18.6 ±3.1 +19.4

a. (HH:MM:SS)

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Temperature Summary

Handling Unit Number

TempTale Location on

Pallet

TempTale Serial Number

Lowest Temperature

Recorded(C°)

Highest Temperature

Recorded(C°)

Time Interval Below 15°Ca

Time Interval Above 30°Ca

Average Temperature Recorded (C°)

Standard Deviation

(C°)

402099962

Top 3464905112 18.4 29.1 --- --- 20.8 2.2

Side 3464905119 13.5 32.6 01:30:00 04:52:30b 20.6 2.7

Front 3464905126 14.0 34.6 01:07:30 06:22:30 20.9 3.0

402099357

Top 3464905115 17.9 27.8 --- --- 20.3 2.1

Side 3464905680 13.4 34.7 01:30:00 06:00:00b 20.4 3.0

Front 3464906489 14.8 33.6 c 06:00:00b 20.4 2.9

402099555

Top 3464906483 17.6 36.1 --- 11:37:30b 21.8 3.6

Side 3464906484 14.4 35.9 c 08:37:30 21.0 3.8

Front 3464906485 14.4 37.6 c 08:37:30 21.1 3.9

402099551

Top 3464906442 17.9 32.0 --- 04:07:30 22.2 2.8

Side 3464906443 15.4 34.8 --- 08:17:00 21.6 3.5

Front 3464906444 15.1 35.1 --- 08:15:00 21.5 3.5

402099964

Top 3464905117 15.9 29.1 --- --- 21.2 2.7

Side 3464905121 15.3 29.2 --- --- 21.0 2.9

Front 3464906431 14.6 29.4 00:22:30 --- 21.5 2.9

402099963

Top 3464906436 18.7 27.0 --- --- 21.6 1.9

Side 3464906476 17.3 30.2 --- 00:22:30 21.3 2.7

Front 3464906486 17.9 30.2 --- c 21.7 2.7

a. (HH:MM:SS)b. Spikes of temperature present during the time interval above 30°C.c. one time point

› Mean Kinetic Temperature1 (MKT) – is a fixed temperature thatsimulates the effects of temperature variation over a period of time.

› It is much more than a number. It is used to reference temperaturesfor stability studies, determine a product’s acceptable range of storagetemperatures, and define “normal” storage conditions on the productlabel.

› The USP defines it as “the single calculated temperature at which thetotal amount of degradation over a particular period is equal to thesum of the individual degradations that would occur at varioustemperatures.

› Thus, MKT may be considered as an isothermal storage temperaturethat simulates the non-isothermal effects of storage temperaturevariations.

791. Mean Kinetic Temperature-Storage vs. Shipping and the Vagaries of Regulatory Requirements Kevin O’Donnell (Contract Pharma July/August 2008)

› Example:

› Wording to use for evaluation of data (including excursions)

Temperatures below +15°C and above +30°C were reported duringtransit. According to gathered data, the minimum and maximum meanand mean kinetic temperatures (MKT) were +9.8°C and +10.4°C and+16.0°C and 16.4°C, respectively. Based on registered data, batchnumber E was exposed to temperatures thermally equivalent to storingAlpha drug product at +16.0°C for the duration of the shipment. Thistemperature is within the long storage temperature conditions (+15°Cto +30°C).

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› To analyze the route and know the total distance:

› Site: www.gcmap.com

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http://www.gcmap.com/

› To evaluate if a new shipment is covered by previousexercises (worst-case) or if a shipment was sent withoutproper validation,– temp data, shipment routes, minimum quantity of temp monitoring

devices placed in shipment, and climatic zones are evaluated:

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Shipment Route Comparison

Country Route Used Miles (mi)

Kuwait SJUa-MIAb-LHRc-AUHd-KWIe 9,414.56

Qatar SJU-MIA-LHR-QTAg 8,694.50

Saudi Arabia SJU-ANUh-LEWi-LHR-JEDj 8,351.86

Validated Route to Saudi Arabia SJU-NY-LHR-DXBk/UAE (Saudi Arabia) 9,099.77

Validated Route to Jordan SJU-NY-LHR-DXB/UAE-AMM (Jordan) 9,739.43

a. SJU = San Juan, b. MIA = Miami, c. LHR = London, d. AUH = Abu Dhabi, e. KWI = Kuwait, f. AMM = Amman, g. QTA = Qatar, h. ANU = Antigua, i. LEW = Maine, j. JED = Jedah, k. DXB = Dubai

› What contributes to Temperature Excursions DuringTransport?– Transfer of product many times during transport– Extreme temperature

› Time in Tarmac› Containers in extreme temperature

– Mishandling› Lack of instructions› Human Error

– Delays› Customs› Transportation Changes› Weather› Seasons

How to Manage Deviations / Events and Excursions?

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› What contributes to Temperature Excursions DuringTransport?


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Poor execution of the Shipping

Better execution of the Shipping

› In terms of Risk, how can we minimize risk to the Product during transportation?– Communication with carriers and forwarders

– Knowledge of Product Stability

– Good Stability Studies and/or Extreme Temperature Condition Studies to demonstrate robustness of the product

– Appropriate Product protection such as Active Containers and Passive Containers


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› If a deviation/event and/or excursion occurs: – Document and notify all impacted parties: carrier, transportation

provider, manufacturing site… Root cause analysis must include from pack-out to delivery (i.e. from packaging site to carrier (air/ocean/ground – including all stops) to site of delivery.

– CAPA implementation

– Monitor to assure effectiveness of actions taken to prevent recurrence.


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› Are managed and evaluated the same as data evaluated per Shipping Study Protocol.

› Content of the Assessment– Background

– Technical Evaluation

– Conclusion


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Develop an Effective Protocol for Conducting Transportation Studies … 12... · Develop an Effective Protocol for Conducting Transportation Studies 12/8-10/15 1. 2 References ...

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