Develop an Effective

Protocol for Conducting

Transportation Studies

Karem Y. Monge Sepúlveda

MS Physics, CQA
Senior Scientist-Technical Services
12/8-10/15 Mylan LLC 1
 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 2
General Information

3
 What is a Cold Chain Process
(Transportation of Product)?
› 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.
4
 Why is it necessary?
Some medicinal products require storage under controlled temperature
in order to maintain product quality. In addition to those labeled for
refrigerator or freezer storage, some products are stable at controlled
room temperature but may suffer degradation at temperature of 30°C or
above 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 5
To What Does Cold Chain Management
Applies?
› 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.

6
Acts, Rules, and Regulations for Cold Chain
Management?
› ICH Q1(R2) – Section 2.2.7 Storage Conditions
A drug product should be evaluated under storage conditions (w/
appropriate tolerances) that test its thermal stability, and if
applicable, its sensitivity to moisture or potential for solvent loss.

The storage conditions and the lengths of studies chosen should be

sufficient to cover storage, shipment, and subsequent use.

Data from accelerated storage conditions and, if appropriate, from

the intermediate storage conditions can be used to evaluate the
effect of short-term excursions outside the label storage conditions
(such as might occur during shipping).

7
Acts, Rules, and Regulations for Cold Chain
Management?
› Who Annex 5 - Definitions
… The data thus obtained, in addition to those derived from real-time
stability studies, may be used to assess longer term chemical effects
under non-accelerated conditions and to evaluate the impact of short-
term excursions outside the label storage conditions, as might occur
during shipping…

› FDA, CFR 21 Part 203.32

States that manufacturers, authorized distributors of drugs and their
representatives should store and handle all drug samples under
conditions that maintains their stability, integrity, and effectiveness and
ensure that the drug samples are free of contamination, deterioration
and adulteration.
8
Acts, Rules, and Regulations for Cold Chain
Management?
› EU Guidance (94/C63/03)
“The Quality System operated by Distributors (wholesalers) of
medicinal products should ensure that storage conditions are
observed at all times, including during transportation…

…Medicinal products requiring controlled temperature storage should

also be transported by appropriate specialized means...

9
Acts, Rules, and Regulations for Cold Chain
Management?
› 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

10
Acts, Rules, and Regulations for Cold Chain
Management?
› 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.

1. Cold Chain Management-An Essential Component of the Global Pharmaceutical Supply Chain, R. H. Bishara 11
(2006-American Pharmaceutical Review)
Acts, Rules, and Regulations for Cold Chain
Management?
› 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 Regulatory
Citations are related to: monitoring devices and their
locations, 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 of
the cold chain of imports, and maintenance of the cold chain
to the patient level.

12
Acts, Rules, and Regulations for Cold Chain
Management?
› Regulatory Trends and Expectations (Cont’d):
– Trends (Cont’d)
Heightened priority of Patient Safety.
SOPs and records for shipping and receiving are available and
contain the following:
• Shipping configuration and type of protective packaging
• Labeling requirements (storage conditions, special
instructions 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 on
the shipment has been tampered with and that there are
no damaged containers
• Evidence that shipping requirements (e.g. temperature
control) have been met. 13
Acts, Rules, and Regulations for Cold Chain
Management?
› Regulatory Trends and Expectations (Cont’d):

– Expectations

Stability studies to support temperature excursions

Qualification (Verification) for seasonal shipping configurations
and load size
Monitoring of shipping temperatures to ensure product quality

14
Transportation Study

15
 Pre-requisites and Requirements for a
Shipping Study
› Why prepare your study to minimize temperature
excursions?
– 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, the
greater the risk to the product.
› Thus, in order to mitigate the risk, manufacturers need to
understand every aspect of the distribution chain.
– Evaluate data from long-term and accelerated stability studies,
temperature excursion studies and/or temperature cycling to
predict the impact of temperature excursions on product quality
during transportation process.
– Understand the responsibilities of shipper, receiver, and
manufacturing site to quickly communicate excursions for resolution
as quickly as possible. 16
 Pre-requisites and Requirements for a
Shipping Study
› 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 product
robustness
– Temperature Sensitivity
– Quantity of temperature monitoring devices needed and time range

17
 Pre-requisites and Requirements for a
Shipping Study
› 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 and
established (duration)
– Vibration effects on material / product being shipped
– Effects on containers and venting (air pressure cycles)
– Physical Stresses – crushing, handling, dropping, leakage
from/onto, package orientation, package placement
– Security – inspection, tampering, radiation exposure

18
 Pre-requisites and Requirements for a
Shipping Study
› Considerations in the protection of the product during
transportation
– 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 of
transportation – qualified protective packaging such as a D-
Container

19
 Principles of Validation
› Generally speaking, the supply chain cannot be “validated”;
however the principles of validation can be used to qualify
portions of the supply chain.

Critical Components of Qualification

› Component Qualification
– Establishes confidence that ancillary component systems are
capable of consistently operating within established limits and
tolerances.
› additional means used in combination with the basic transportation unit
maintain the required temp during transport
– Critical components are those with quality parameters that may
reasonably be expected to affect the acceptance criteria of a cold
chain shipment (temp monitors, insulated shipping containers,
refrigerants such as a gel pack.
– Most commonly included in the DQ and OQ. 20
 Critical Components of Qualification
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 the
product, 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 the
form of the basic transportation as the overall thermal mass that must
be temperature-controlled)
› Expected ambient profiles
› Material requirement and restrictions
› Marketing requirements
› User requirements 21
 Critical Components of Qualification
› 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 air
conditioning system
› Product shipping configuration with the temperature monitoring
device location
› Type of insulated material / air conditioning system
› Minimum and maximum thermal mass and loads
› Location of temperature monitoring device location.

22
 Critical Components of Qualification
› Operational Qualification (OQ) and Performance Qualification (PQ)
– Should be performed using designated transport configuration to
provide assurance that product quality is maintained during
transport.
– 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 in
ambient temperatures customary in shipping/distribution over the
route/region and in the temperature/season(s) being qualified.
– Testing done using the same packaging configuration (pack-out) finalized
in the development phase or rationale provided if using other.
– Testing repeated a minimum of three (3) times, using three (3) sample
containers with components, at each set of conditions (load minimum and
maximum or worst-case) and tem cycle (hot and cold or worst-case) is
necessary. 23
 Critical Components of Qualification
› Operational Qualification (OQ) and Performance Qualification (PQ)
– PQ consists of consecutive, replicate field transportation tests to
demonstrate 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 backup
monitor included in each shipping container (inside container temp)
and one primary and one secondary monitor on the outside of each
shipping container (ambient outside temp).
› Protocol must adequately describe the packaging and shipping
processes that will be utilized for commercial shipments
› Routes, modes, seasons, and times representative of commercial
shipping conditions 24
 Critical Components of Qualification
› 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 formally
accomplished by means of approved procedures that will implement
the controls of critical process parameters, which will result in
repeatable, successful transport of medicinal product.
– Training should provide instruction to relevant personnel and
organizations participating in the temp controlled process
concerning the principles of packaging, qualifying, and transporting
temp sensitive medicinal product.

25
 Critical Components of Qualification
› Process Implementation and Training (Cont’d)
– The shipping or receiving area shall be responsible for reviewing
temp monitor data, when monitors are included in shipping
containers, and may approve shipments based on these data when
there are no deviations.
– There shall be procedures for implementing corrective actions in the
case of deviations. The QU, with an evaluation by Technical
Services, shall be responsible for making accept/reject decisions for
shipments w/deviations.
– Change Control
› Quality agreements w/suppliers of cold chain components must
contain wording, which requires that suppliers inform the Site of
any changes in materials, the manufacturing process,
specifications or changes of significance.

26
 Critical Components of Qualification
› Monitoring
– In order to maintain the process in a state of control, process
parameters shall be monitored and trended when sufficient data are
available.
– 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 periodically
in distribution of products to customers.
› Analysis of weather data obtained either from historical
repositories or from shipments designed to measure shipping
route ambient temps.

27
 The Importance of Stability
› Why perform Stability Studies?1
– The purpose of Stability testing is to provide evidence of how the
quality of an API or FPP varies with time under the influence of a
variety of environmental factors such as temperature, humidity and
light, as well as to establish a retest period for the drug substance
or a shelf life for the drug product and recommended storage
conditions.
– The choice of test conditions is based on an analysis of the effects
of climatic conditions in the three regions of the EC, Japan and the
United States.
– In general, a drug substance should be evaluated under storage
conditions (with appropriate tolerances) that test its thermal stability
and, if applicable, its sensitivity to moisture. The storage conditions
and the lengths of studies chosen should be sufficient to cover
storage, shipment, and subsequent use.
1. ICH Q1A (R2) and WHO Annex 2 28
 The Importance of Stability
› Why perform Stability Studies?1
– The stability program also includes the study of product-related
factors that influence its quality, for example, interaction of API with
excipients, container closure systems and packaging materials. In
fixed-dose combination FPPs (FDCs) the interaction between two or
more 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%RH 12 months
or
30°C±2°C / 65%RH±5%RH
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.
29
1. ICH Q1A (R2) and WHO Annex 2
 The Importance of Stability
› 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

1. ICH Q1A (R2) and WHO Annex 2 30

 The Importance of Stability
› 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

1. ICH Q1A (R2) and WHO Annex 2 31

 The Importance of Stability
› 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.

1. ICH Q1A (R2) and WHO Annex 2 32

 – The choice of test conditions are to be defined on an analysis of the
effects of climatic conditions.
Storage
Climatic Zone Definition Conditions Countries1, 2
ºC
Temperate Climate Quebec-Canada, Japan, USA, Buenos Aires-Argentina,
I (Cold winter, mild 21 / 45 Amsterdam-Netherlands, London-England, Seoul-Korea,
summer) Incheon-Korea, Russia, Switzerland, Ukraine, China
Sub-tropical and
Miami-USA, New York-USA, Atlanta Georgia-USA,
Mediterranean
Santiago-Chile, Nablus-Palestine, Rome-Italy, Milan-Italy,
climates(Semiarid,
Catania-Italy, Mexico, Peru, (Tel Aviv Yafo) Israel,
II Mediterranean, Marine 25 / 60
Uruguay, Bolivia, Afghanistan, Iran, Egypt, Algeria, EU,
W. Coast, Humid
Algeria, Morocco, Namibia, South Africa, China, Sydney-
Subtropical, Tundra,
Australia
Highlands)
Iraq, Amman-Jordan, Karachi-Pakistan, Saudi Arabia3,
III Hot, Dry climate (Arid) 30 /35
United Arab Emirates, Qatar, Kuwait, India
Barbados, Belize, Brazil, Costa Rica, Dominican Republic,
IVa Tropical Dry 30 / 65 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,
IVb Tropical Wet 30 / 75 Bangladesh, Manila-Philippines, Singapore, Taiwan,
Taipei-Taiwan, Kuala Lumpur-Malaysia, Saigon-Vietnam,
33
Colombo-Sri Lanka, Madagascar
– The choice of test conditions are to be defined on an analysis of the
effects of climatic conditions. (Cont’d)
1,2 Guide values for individual climatic zone
Criteria I II III IV

Mean Annual Temp measured in

Up to 15 > 15 - 22 > 22 > 22
open air (oC)

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

Mean Annual water vapour partial

Up to 11 > 11 - 18 Up to 15 > 15
pressure (mbar)

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 55ºC
in 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
– The choice of test conditions are to be defined on an analysis of the
effects of climatic conditions. (Cont’d)

Seasons
Months
North Hemisphere South Hemisphere

September - November Fall (F) Spring (Sp)

December - February Winter (W) Summer (S)

March - May Spring (Sp) Fall (F)

Summer (S) Winter (W)

June - August

35
 The Importance of Stability
› 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 during
storage.
– Chemical profile of product exposed at temperature extremes as a
projection through time and considering the Stability Program.
– Studies to support short-term temperature excursions on the
stability profile of the product.
› Temperature stress studies for a period of time at a certain
temperature. Then, samples are placed in Accelerated Storage
(ACC – 40°C±2°C / 75%±5%RH) conditions in the Stability
Program.

36
37
 Examples of Containers and Use of Data
Loggers
› Data Loggers
– Programmable temperature and humidity monitors to track and
collect data about temperature sensitive shipments, usually NIST®
traceable and single use.

Sensitech TempTale4 Marathon Products c\temp data Logger

38
 Examples of Containers and Use of Data
Loggers
› Containers
– Air Cargo
– Ocean Freight - insulated container
– Envirotainer - thermostat controlled heat exchanger powered by
batteries and using dry ice as coolant.

Air cargo cartons

(D-Container type)
Envirotainer (RKN t2 type)

Ocean Freight container

(ULD type)

39
 Examples of Containers and Use of Data
Loggers
› 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

40
 Examples of Containers and Use of Data
Loggers
› 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

41
 Choose: Active or Passive Systems?
› 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.
1. Temperature-Controlled Packaging Systems: Active or Passive? A. Roskoss (Innovations on Pharmaceutical Technology
42
Issue
37, 2011)
 Choose: Active or Passive Systems?
› 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 significant
handling restrictions, providing more potential carriers and routes to become
available 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.

43
Documentation

44
 How to Write an Effective Protocol?

› 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.

45
 How to Write an Effective Protocol?
› 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
46
 How to Write an Effective Protocol?
› 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
47
 How to Write an Effective Protocol?
› 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
48
should read effortlessly.
 How to Write an Effective Protocol?
› 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.

49
 How to Write an Effective Protocol?
› 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.
50
 How to Write an Effective Protocol?
› 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 51
 How to Write an Effective Protocol?
› 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.

52
 How to Write an Effective Protocol?
› 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

53
 How to Write an Effective Protocol?
Clear Concise English “The Golden Rule” Cont’d
› Verbs › Verbs
– In Reports: – In Instructions:
› Use Passive Voice to › Use Present Tense for
report actions and results instructions
› Use the Past Tense to
report actions and results › Pretend everything
› Optionally, use the happens in the Present
Present Tense for Tense
discussion, conclusions, › Also, describe
and recommendations processes in Present
› Above all, BE Tense
CONSISTENT › Use the Imperative, if
possible
› Place the Imperative at the
start of the instruction, if
possible 54
 How to Write an Effective Protocol?
› 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
55
– Expand abbreviations the first time they occur
 How to Write an Effective Protocol?
› 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 56
 How to Write a Shipping Study Protocol?
› 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 57
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69
70
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How to Analyze Data?

73
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75
› Confirmation, with photos, that shipment arrived in good
order (visual inspection).
› Confirmation that all temp monitoring devices used were
found 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 acceptance
criteria (temp profile) and any permitted temp excursions.

76
 Handling Lowest Highest Time Time Average Mean
TempTale Standard
Unit and/or Temperatur Temperatur Interval Interval Temperatur Kinetic
Serial Deviation
LD9 e Recorded e Recorded Below Above e Recorded Temperatur
Number (ºC)
Number (ºC) (ºC) +15ºCa +30ºCa (ºC) e (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 1 day,
+9.3 +36.1 01:52:30 +18.4 ±2.9 +19.0
03:00:00
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
1 day,
402356056 3446923381 +9.8 +42.3 02:37:30 +18.7 ±3.1 +19.3
09:22:30
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 77
a. (HH:MM:SS)
 Temperature Summary
Lowest Highest
TempTale Average Standard
Handling Unit TempTale Temperature Temperature Time Interval Time Interval
Location on Temperature Deviation
Number Serial Number Recorded Recorded Below 15°Ca Above 30°Ca
Pallet Recorded (C°) (C°)
(C°) (C°)
Top 3464905112 18.4 29.1 --- --- 20.8 2.2
402099962 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
Top 3464905115 17.9 27.8 --- --- 20.3 2.1
402099357 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
Top 3464906483 17.6 36.1 --- 11:37:30b 21.8 3.6
402099555 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
Top 3464906442 17.9 32.0 --- 04:07:30 22.2 2.8
402099551 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
Top 3464905117 15.9 29.1 --- --- 21.2 2.7
402099964 Side 3464905121 15.3 29.2 --- --- 21.0 2.9
Front 3464906431 14.6 29.4 00:22:30 --- 21.5 2.9
Top 3464906436 18.7 27.0 --- --- 21.6 1.9
402099963 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

78
› Mean Kinetic Temperature1 (MKT) – is a fixed temperature that
simulates the effects of temperature variation over a period of time.
› It is much more than a number. It is used to reference temperatures
for stability studies, determine a product’s acceptable range of storage
temperatures, and define “normal” storage conditions on the product
label.
› The USP defines it as “the single calculated temperature at which the
total amount of degradation over a particular period is equal to the
sum of the individual degradations that would occur at various
temperatures.
› Thus, MKT may be considered as an isothermal storage temperature
that simulates the non-isothermal effects of storage temperature
variations.

1. Mean Kinetic Temperature-Storage vs. Shipping and the Vagaries of Regulatory Requirements Kevin O’Donnell (Contract
79
Pharma July/August 2008)
› Example:
› Wording to use for evaluation of data (including excursions)
Temperatures below +15°C and above +30°C were reported during
transit. According to gathered data, the minimum and maximum mean
and 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, batch
number E was exposed to temperatures thermally equivalent to storing
Alpha drug product at +16.0°C for the duration of the shipment. This
temperature is within the long storage temperature conditions (+15°C
to +30°C).

80
› To analyze the route and know the total distance:
› Site: www.gcmap.com

81
› To evaluate if a new shipment is covered by previous
exercises (worst-case) or if a shipment was sent without
proper validation,
– temp data, shipment routes, minimum quantity of temp monitoring
devices placed in shipment, and climatic zones are evaluated:
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

82
How to Manage Deviations / Events and
Excursions?
› What contributes to Temperature Excursions During
Transport?
– 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
83
 How to Manage Deviations / Events and
Excursions?
› What contributes to Temperature Excursions During
Transport? Better execution of the Shipping

Poor execution of the Shipping

84
How to Manage Deviations / Events and
Excursions?
› 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

85
How to Manage Deviations / Events and
Excursions?
› 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.

86
How to Manage Deviations / Events and
Excursions?
› 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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