Development of Injectable Drugs: Technology Transfer and Process Validation Anna Carolina Myers da Silva Luzia Thesis to obtain the Master of Science Degree in Pharmaceutical Engineering Supervisors: Professor José Monteiro Cardoso de Menezes Specialist Patrícia Alexandre Horta Antunes Examination Committee Chairperson: Professor Pedro Paulo De Lacerda e Oliveira Santos Supervisor: Professor José Monteiro Cardoso de Menezes Member of the Committee: Professor Helena Isabel Fialho Florindo October 2017
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Development of Injectable Drugs: Technology Transfer and
Process Validation
Anna Carolina Myers da Silva Luzia
Thesis to obtain the Master of Science Degree in
Pharmaceutical Engineering
Supervisors: Professor José Monteiro Cardoso de Menezes
Specialist Patrícia Alexandre Horta Antunes
Examination Committee
Chairperson: Professor Pedro Paulo De Lacerda e Oliveira Santos
Supervisor: Professor José Monteiro Cardoso de Menezes
Member of the Committee: Professor Helena Isabel Fialho Florindo
October 2017
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Acknowledgments
Firstly, I would like to express my gratitude to Hikma Pharmaceuticals for the opportunity of attaining
this internship. A special thank you to my Professor Dr. José Cardoso de Menezes, coordinator of the
Master’s degree, for all the support and wisdom transmitted during the course as well as the help
establishing my introduction to the company together with Eng Samuel Camocho.
For the past year, I have learnt so much about how a pharmaceutical company functions, due to all the
people I have had the privilege to work with. Eng. Raquel Marques from the Technical Services
department deserves an enormous amount of credit, for her tireless effort and patience. Teaching me
and answering all my questions about technology transfers/ process validations and allowing me to
accompany the compounding process of new products being manufactured for validation on the
production line. Her intelligence and experience are in fact admirable. A huge thank you to Raquel.
I would also like to thank the professionalism and help of my Supervisor at the Wet-chemistry department
Eng. Patrícia Antunes. For everything I learned from her and for making it possible to conduct my thesis
with the New Projects and Technical Services departments. I would also like to thank Eng. Isabel
Cordeiro (Manager) and Rita Pereira (Supervisor) of the New Projects department for allowing me to
conduct the analytical studies of the new products I accompanied and for later choosing me to take part
in the team.
I wish to convey my appreciation to all my colleagues from the Wet-chemistry team with whom I worked
every day for six months, and to my colleagues at the New Projects with whom I am presently working.
Thank you also to João Sousa, an experienced production operator at Hikma for helping me understand
the functionality of the production line 5.
Last but not least, I would like to thank my parents, my grandparents and my friends for all their support.
A special mention to Catarina Reto, Mariana Rodrigues, Catarina Serra, Catarina Lima, Andreia Revêz,
Rita Saúde, Pedro Gonçalo, Teófilo São Pedro and Joana Leandro.
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Abstract
One of the most important aspects in pharmaceutical industries is the manufacturing process. The aim
of the thesis is to contribute to the knowledge about correct validation of processes and successful
technology transfers. Frequently, it is necessary to transfer a technology from a developing site to a
manufacturing site or from one manufacturing site to another for the validation to be completed.
In order to appropriately plan a manufacturing process, quality by design should be followed. Prior
knowledge has to be gained through research and development studies and risk management tools. By
identifying critical quality attributes and critical process parameters it is possible to evaluate risk
scenarios during production and their level of impact. A suitable control strategy is then established
leading to consistent production of quality products. Innovative approaches such as process analytical
technology enable a real-time monitoring and control of the critical aspects of a manufacturing process.
New products transferred to Hikma Portugal are presented including the process design, risk
assessment, evaluation of the preferable conditions for the process at the new site and scale-up.
Keywords: process validation, technology transfer, quality by design, risk assessment, process
analytical technology, scale-up
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Resumo
Na indústria farmacêutica, definir um processo de produção adequado é um dos aspetos mais
importantes. O objetivo da tese foca-se em contribuir com conhecimento sobre a validação correta de
processos de produção e transferências de tecnologia. De modo a completar uma validação, pode ser
necessário transferir uma tecnologia de um local de investigação e desenvolvimento para um local de
produção, ou de uma fábrica de produção para outra.
A fim de desenvolver adequadamente um processo de produção, a abordagem “quality by design” deve
ser utilizada. O conhecimento prévio relativamente ao produto e ao processo é obtido através de
estudos de investigação e avaliação de risco. Identificando os atributos de qualidade críticos e os
parâmetros críticos do processo é possível avaliar situações de risco que possam ocorrer durante a
produção e o seu nível de impacto. Um sistema de controlo adequado é então estabelecido resultando
em manufatura de produtos com qualidade consistentemente. Abordagens inovadoras, como a
tecnologia analítica de processo, permitem a monitorização e controlo em tempo real dos aspetos
críticos de um processo de produção.
São apresentados dois novos produtos transferidos para a fábrica Hikma em Portugal, incluindo o
desenho do processo, avaliação de risco, análise das condições preferenciais do processo na nova
instalação e aumento de escala.
Palavras-chave: validação de processo, transferência de tecnologia, “quality by design”, avaliação de
risco, tecnologia analítica de processo, aumento de escala
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Table of Contents
Acknowledgments .................................................................................................................................. i
Abstract ................................................................................................................................................. iii
Resumo................................................................................................................................................... v
Table of Contents ................................................................................................................................ vii
List of Acronyms .................................................................................................................................. ix
List of Figures ...................................................................................................................................... xii
List of Tables ....................................................................................................................................... xiv
Table 15 - Risk assessment for the technology transfer of product B from Bedford to Hikma regarding
filtration and filling .................................................................................................................................. A6
Table 16 - Risk assessment for the scale-up to commercial size regarding the preparation tank,
dissolution times, mixing speeds and filtration of product B .................................................................. A7
Table 17 - Risk assessment for the scale-up to commercial size regarding the filtration and actual
production yield of product B ................................................................................................................. A8
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1. Introduction
1.1. Aim of the thesis
The aim of the thesis is to contribute to the knowledge about development of injectable pharmaceutical
products. In particular, how technology transfer and Process Validation (PV) is developed and performed
in pharmaceutical industries, specifically Hikma Pharmaceuticals Portugal. The purpose is also to
examine the possibility of improving the control strategy of submission batches, so that the risk of failed
batches for validation is reduced as well as the following commercial batches.
1.2. Outline of the thesis
The thesis will begin by a literature review based on platforms from organisations such as International
Council for Harmonisation of technical requirements for pharmaceuticals for human use (ICHs), World
Health Organisation (WHO), Food and Drug Administration (FDA) and European Medicines Agency
(EMA). The literature review is also based on articles regarding technology transfers, PV concept and
scale-up. Hikma’s documentation – Standard Operating Procedures (SOPs) – concerning this matter
will also be used.
The thesis is followed by a description of Hikma’s facilities and lines of production, in more detail line 5,
because the new products in development that will be mentioned were produced in this line.
Two practical examples of products for validation are presented. Starting by a detailed description about
the transfer of the injectable products to Hikma PT from Hikma located in the United States (US)
denominated Bedford. The process is explained, including the compounding and filling on line 5. The
evaluation activities performed during production of the submission batches are mentioned together with
the relevant results. Scale-up plan for product B is presented.
The last part includes an investigation about the possibility of control strategy improvement, so that the
risk of failures during validation and consequently during commercial manufacturing are reduced.
Process Analytical Technology (PAT) is taken into consideration – the Critical Process Parameters
(CPPs), Critical Quality Attributes (CQAs) and Critical Material Attributes (CMAs) of the selected new
products in development at Hikma are analysed.
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2. Literature review
2.1. Technology transfer
2.1.1. Definition
The term technology transfer can be defined as the movement of knowledge, skill, organisation, values
and capital from the point of generation to the site of adaptation and application. In the pharmaceutical
industry, technology transfer refers to the processes that are needed for successful progress from drug
discovery to product development, to clinical trials, to full scale commercialization or it can be the
process by which a developer of technology makes its technology available to a commercial partner that
will exploit the technology. In general, technology transfer can be used to refer to movements of
technology from the laboratory to industry, developed to developing countries, or from one application
to another domain. (Feifeit 2008)
The transfer is successful if the receiving unit can routinely reproduce the transferred product, process
or method against a predefined set of specifications as agreed with a sending unit or a development
unit. (Al Ghailani 1995)
2.1.2. Classification
Technology transfer can be classified into vertical and horizontal technology transfer. Vertical transfer
refers to transfer of technology from basic research to applied research, then to development and finally
to production. Horizontal transfer refers to the movement and use of technology used in one place,
organisation, or context to another. (Mansfield 1975)
Vertical tech-transfer can be seen as internal technology transfer and horizontal tech-transfer as external
technology transfer. On this point of view, vertical technology transfer is considered a managerial
process of passing a technology from one phase of its lifecycle to another. Horizontally transfer
reinforces that it may be possible to transfer technology in locality terms at any stage of the technology
lifecycle. (Souder 1990)
The transfer can further be divided in other categories: material transfer, design transfer, and capacity
transfer. Material transfer refers to the transfer of a new material or product while design transfer
corresponds to the transfer of designs and blueprints that can facilitate the manufacturing of the material
or product by the transferee. Capacity transfer involves the transfer of know why and know-how to adapt,
and modify the material or product to suit various requirements. (Steenhuis 2002)
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2.1.3. From drug discovery and development process to
technology transfer
Technology transfer, as explained previously, is a process to transfer information and technologies
necessary to manufacture quality drug product consistently or it can be the process of taking an
invention from its inception in a laboratory to a commercialized product.
The successful technology transfer from Research and Development (R&D) (the transferring site), to
the commercial production site (the receiving site), is a critical process in the development and launch
of a new medicinal product. It can be extremely costly for a company if something goes wrong during
the transfer process, resulting in delays. Furthermore, it can take increased resource, time and cost to
make corrective actions following an unsuccessful transfer. Progressive pharmaceutical companies are
therefore placing more attention to streamlining and optimising their technology transfer process to
ensure the rapid and successful introduction of a new product to the market. The ideal situation is to
complete the transfer to the production site at an affordable cost. (Ghafaripour 1999)
Technology development has to pass by three stages: the development of a new science, the link
between the new science and technology and the technology being put into products. The drug quality
is designed based on data concerning efficacy and safety obtained from various studies in preclinical
phases and data concerning efficacy, safety and stability of drug products obtained from clinical studies.
The phase I, clinical studies involve small scale studies in patients, they are provided in the form of a
non-optimized formulation, quite different from the intended commercial formulation. There is a high
probability that the studies do not proceed to full development due to toxicity findings or clinical findings
(safety, efficacy and pharmacokinetics/bioavailability). Phase II and III involve longer term safety and
clinical studies in larger groups of patients suffering from the targeted disease. During full development,
the synthetic route for the drug substance is optimized and the manufacturing process is scaled up and
fixed.
If sufficient drug substance is available and the phase III supplies are very large, it may be preferable to
scale-up the manufacturing process to production scale and transfer the process to the commercial
production site and use the supplies from there. A potential risk of transferring early to production is that
all the development work has to be done earlier, the formulation has to be completed as well as the
manufacturing process design. After transferring the process to production it is still possible to perform
adjustments, however it involves documented change controls. Starting the technology transfer before
initiating the phase III studies is also a slight unsafe approach because there is still a relatively high risk
involved during phase II caused by failures related to efficacy and clinical safety.
Regulatory authorities such as FDA, the Medicines and Healthcare products Regulatory Agency
(MHRA) in the United Kingdom (UK) and the European Agency for the Evaluation of Medicinal Products
(EMEA), require three phases of clinical trials and sufficient data to show that the new drug product can
be licensed as safe, effective and of acceptable quality. Once the phase III clinical trials are completed
successfully and the commercial manufacturing process has been transferred from R&D to production
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site, a regulatory submission can be made. It is important to take into consideration that the technology
transfer, apart from the information related to the process manufacturing, also involves the development
and successful transfer of the analytical and microbiological test methods for the drug substance and
drug product that will be used by the Quality Control (QC) departments at the commercial production
site.
To assure the drug quality, it is desired to make sure what, when and why information should be
transferred to where and by whom and how to transfer, then share knowledge and information of the
drug product between transferring and transferred parties. (Gupta 2012)
As a summary, technology transfers happen mainly between these three points: research phase,
development phase and production phase.
Research phase
The research site is responsible for the correct pharmaceutical design of the drug. This phase includes
the study of the components/product efficacy, guarantee the avoidance of adverse reactions, assure the
drug stability and analyse the data available to achieve a better knowledge about the product. (Gorman
2002)
Development phase
In order to manufacture drugs with qualities as designed, it is required to establish an appropriate
manufacturing process at a small scale and detect variability factors to assure that the scale-up for
submission and validation purposes will be performed without difficulties. The upper and lower limits of
the manufacturing process including composition and parameters should be challenged during
development. (Patel 2009)
Production phase
To assure the consistency between development and manufacturing, the transferring party in charge of
development should fully understand what kind of technical information is required by the receiving party
in charge of manufacturing. An appropriate evaluation method to determine whether a drug to be
manufactured meets the quality of design should be executed. In case the product is similar to others
before produced, it is fundamental to study the information about the process maintained by the
manufacturer. (Gibson 2001)
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2.1.4. Reasons for technology transfer
A developer of technology makes its technology available to another person to exploit for several
reasons. It can occur that the original inventor of technology may have the resources to conduct early-
stage research such as animal studies and toxicology study, but does not have the resources to take
technology through its clinical phases. Another frequent situation is having the resources to develop the
product, however it might not be sufficient to take the technology through its regulatory phases, for this
reason the developer must collaborate with another organization to take the product into market.
The developer of the technology may have developed the product to a state almost ready to launch,
nevertheless the manufacturing capability and resources available may only be suitable for small scale
production. A partnership with an organization with a large scale capability is necessary.
It can also happen that a full development of the technology has been completed with regulatory
approvals and product registrations for the product to be sold, however it can lack the marketing and
distribution channels. Due to this deficiency a collaboration with another organization which has that
capability is necessary. (Patil 2010)
2.1.5. Importance of technology transfer
It has been recognized that the transfer of technology is essential for the process of economic growth,
and that the progress of both developed and developing countries depends on the efficiency of such
transfer. A firm and its partners collaborating in the technology transfer will gain financial and strategic
benefits, the means not available at one site compensates the resources available in another. Working
in partnership makes it possible to accomplish every stage. The importance of technology transfer has
also stimulated university industry technology transfer.
In the pharmaceutical industry, the intersection between business and science is both essential and
critical to the drug discovery and development process for a new medicinal product. Technology transfer
allows the link between R&D, process development and production for commercialization. If it is
implemented thoughtfully then production process runs efficiently, the risks during production are
minimized and a robust process for routine commercial manufacturing is achieved.
Appropriate technology transfer is essential to upgrade the quality of design to be the quality of product,
and ensure stable and high quality of the product. (Osman 1999)
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2.1.6. Factors influencing technology transfer
Drivers
Technology transfer has several advantages. As mentioned it allows a promising market scale because
if a specific process is transferred to a larger country the business and marketing potential is greater.
The countries have a supportive environment that includes strong intellectual property and enforcement
to successfully attract imported technology, which facilitates the transfer. Factors as skilled workforce
working together such as engineers and managers also contribute to efficiency in the results. Increased
information exchange including effective systems that identify who is interested in purchasing the
technology and entities willing to transfer their technology are easy ways to facilitate the task.
The prospect of technology transfer can be very desirable to local pharmaceutical manufacturers even
in another viewpoint. The technology, new machinery, training, among other transfer additional benefits
can then be applied profitably for other production purposes. (Donald et al 1995) (Akhavan 1995)
Barriers
Technology transfer can face different difficulties. For example, there is a need of skilled labour however
the unattractive conditions of service are a negative contributor.
In the cases where the knowledge and awareness were not accomplished at a high level by the
developer of the technology, the transfer to the new site is more complex. The lack of government focus
at times towards the technology transfer approach and the high cost for prequalification can also bring
complications, monetarily. The funding on important areas of research should also be higher.
Furthermore, there are controls and restrictions on technology exportation established by national
security which makes it harder to perform the transfer internationally. Another problem found is the
reduced access to online scientific journals, for the R&D site it can raise difficulties during the
development process. (Ortega 2009)
Approaches to overcome obstacles
In order to overcome the problems faced by technology transfer certain measures can be taken. For
instance, it is preferable to commercialize publicly funded technologies so that the costs involved are
not as high. Political stability will influence the rate of inward technology transfer and a good leadership
is essential for a strengthened healthcare system. Incentives designed to encourage technology transfer
such as adequate capital markets should be implemented.
Regarding the difficulty of not having access to important scientific discovers online, research tools for
patents and an international treaty on scientific access could solve the problem. (Madu 1989)
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2.1.7. Team and training
The technology transfer team is meant to develop and implement a methodology that ensures the
effective and efficient transfer of robust and candidate production processes from development to
manufacturing.
The team is trained on the technology transfer process, so that each member is familiar with both the
business methodology to be used and the technical aspects of the process being transferred. Each
member must understand process tools, to help organize and assemble numerical data, assign action
items and identify areas of weakness or omission. Successful technology commercialization depends
on a skilled workforce in management, production, sales, distribution, and support.
In order to obtain a successful project, it is necessary to implement an effective training for all involved
in the new process, including production operators and regulatory team members which will prepare the
submission. The training is applied on the transfer process and consequently provides a good
knowledge about the process technology. In accordance to the current Good Manufacturing Practices
(GMP) requirements, all training has to be documented and all members which interact with the new
technology have to be trained. (Souder 1990)
2.1.8. Documentation
The documentation for technology transfer includes content for transferring and transferred parties, it
should be always available and traceable. Task assignment and responsibilities should be clarified. The
Quality Assurance (QA) department at the manufacturing site checks and approves the technology-
transfer documentation. Information from the transferring site is essential so that the technology transfer
team can better evaluate options and can distinguish the critical from the incidental. The reasons for the
selection of particular unit operations, equipment, and conditions, should be well described in the
documentation so that every step can be clearly understood. (Ali 2012)
In the cases where the transfer happens from R&D site to manufacturing site, the technology transfer
dossier provided to the production site includes documentation for the transfer of the analytical methods.
It contains information about formulation and drug product such as the Master Formula Card (MFC)
which comprises the product name, strength, generic name, shelf life and markets of interest. It also
includes the master formula (formulation, steps of manufacturing process and environment conditions
required) and the master packaging card (packaging type, material used for packaging, stability and
shelf life). The specifications and Standard Test Procedure (STP) have to be included together with
information about the Active Pharmaceutical Ingredient (API) and excipients profile, in-process
parameters and finished product details. (Dogra 2013)
Table 1 presents the data included in the existing types of documents for technology transfer.
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Table 1 – Information contained within technology transfer documentation (Dogra 2013)
R&D report Product
specification file
Technology
transfer plan
Technology
Transfer Report
(TTR)
Info
rmati
on
Development of the new
drug
Product
manufacturing
Items and contents
of technology to be
transferred
Activities and results
performed by
transferring party
Raw materials, API and
impurities
Assurance of
operation safety
Procedures of
transfer and transfer
schedule
Knowledge to
achieve a
successful transfer
Synthetic route, formula
design
Environmental
impact assessment
Judgment criteria for
the completion of
the transfer
Stability data Costs
Specifications and test
methods
2.2. Process validation
2.2.1. Definition
Validation means “action of proving effectiveness”. There are several similar definitions, on the first
stages it can be defined as collecting and evaluating data. (Sarvani 2013)
The European commission, FDA and ICH consider PV as documented evidence with high degree of
assurance that a process, operated within established parameters, can perform effectively and
reproducibly to produce a medicinal product meeting its predetermined specifications and quality
attributes. (WHO 1996)
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2.2.2. Resources required
A validation requires three main aspects: time, financial means and skilled labour. It can take a lot of
time to complete all the stages, however rigorous time schedules will have to be accomplished to assure
the availability of the product in the market when planned. A high financial plafond must be available by
the manufacturing site because validation requires specialized personnel and expensive technology.
The need of a multidisciplinary team depends on the process and product to be validated, it comprises
quality assurance, engineering, manufacturing and other disciplines. (WHO 2006)
2.2.3. Need and importance
Validation in itself does not improve processes however it confirms the efficiency of the developed
processes and proves that they are under control. It can help to reduce the quality costs, which are
divided into four categories: preventive costs, appraisal costs, internal failure costs and external failure
costs.
A scientifically studied and controlled validated process makes it less likely that defective products are
sent to the market and also reduces customer complaints. It is proven that batches fail less, as a
consequence the output is increased and productivity is higher. Another important quality that results
from validation is the increase in safety. Tested and approved equipment and materials during
qualification and validation assure that the product is produced safely. The obligation by regulatory
governments to calibrate certain equipment, and to perform periodic maintenance also improves the
security. Furthermore, there is an advantage for employees, their execution is improved due to the
previous awareness of the process during the validation.
Government regulation obliges compliance with validation requirements to obtain approval for
manufacture and to introduce new products, this helps to assure that all processes implemented are
controlled and suitable. (Keyur 2014)
2.2.4. Approaches to validation
Validation can be prospective, concurrent, retrospective or revalidation depending on when it is
performed in relation to production.
Prospective validation
Prospective validation is adopted for when new drug products are introduced. It is carried out in the
development stage, a risk analysis of the production process is made. The process is broken down into
individual steps which are evaluated based on data from experimentation to determine if they might lead
to critical situations. If critical points are found, the risk is evaluated and the potential causes are
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investigated. Trials are performed, and if the results are acceptable, the process is suitable. (Sarvani
2013)
Unsatisfactory processes are modified and improved until a validation demonstrates that they are
acceptable. This type of validation limits the risk of errors occurring on the production scale. (WHO 1996)
Concurrent validation
Concurrent validation takes place during normal production. This method is effective if the development
stage has resulted in sufficient knowledge and understanding of the process. The first three production
scale batches must be well monitored, the specifications of subsequent in-process and final tests are
based on the monitoring results. (WHO 1996)
With the documented results the process is proven to be in a state of control. Concurrent validation with
a trend analysis including stability should be done throughout the lifecycle of the product. (Sarvani 2013)
Retrospective validation
Retrospective validation is chosen for established products with stable processes. This type of validation
comprises experience of production, it assumes that composition, procedures, and equipment remain
unchanged. The experience and the results of in-process and final product testing are then evaluated.
Failures that occur in production are analysed to determine the limits of process parameters. (Sarvani
2013)
A trend analysis is conducted to determine the extent which the process parameters are within the
permissible range. This mean of validation should never be applied to new processes or products, it is
used only in special circumstances. Retrospective validation can be useful in establishing priorities for
the validation programme. If the results of a retrospective validation are positive, it indicates that the
process does not need immediate consideration and may be validated normally. (WHO 1996)
Revalidation
Revalidation is used when it is necessary to prove that intentional or unintentional changes in the
process or in the process environment, do not adversely affect process characteristics and product
quality. Revalidation can be executed after a change with impact on product quality, or periodically at
scheduled intervals.
When the revalidation occurs after a change, it is necessary to implement the alterations affecting the
manufacturing or standard procedure and perform again the same tests made in the first validation.
Each modification should be reviewed by a qualified validation group to conclude if it is sufficient to opt
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by revalidation, and if it is, in which extent. Unexpected changes and deviations can be observed during
self-inspection or audit, or during the continuous trend analysis of process data.
The changes are usually on starting materials, physical properties (density, viscosity, particle size
distribution and crystal type of the active ingredients or excipients), packaging material (for example
replacing plastics by glass), process (changes in mixing time, drying temperature and cooling regime
can affect process steps and product quality), equipment, production area and support system. The
rearrangement of manufacturing areas or support systems such as ventilation may result in changes in
the process, revalidation may be necessary predominantly in sterile products manufacturing.
When the revalidation is periodic, scheduled times for analysis are organised even if no changes have
been made (just for caution). This happens because process changes may occur gradually even if
experienced operators work correctly according to established methods, so as equipment which can
also have continuing changes.
For scheduled revalidation the following points have to be checked: changes in the master formula,
methods, batch sizes, analytical control methods and if it impacts the product; confirmation that
calibrations and preventive maintenance has been made in accordance with the established programme
and time schedule; cleaning programmes have been carried out and SOPs have been updated correctly
and implemented.
Periodic revalidation is based on a review of historical data (in-process and finished product testing after
the latest validation) to verify that the process is under control.
In some processes, such as sterilization, additional process testing is required to complement the
historical data. (Sarvani 2013)
So basically, there are two approaches to validation, one based on evidence obtained through testing
(prospective and concurrent validation), and one based on the analysis of accumulated/ historical data
(retrospective validation). Whenever possible, prospective validation is preferred. Retrospective
validation is no longer encouraged and is, in any case, not applicable to the manufacturing of sterile
products. (WHO 1996)
2.2.5. Scale-up and risk assessment
Scale-up of pharmaceutical manufacturing processes demand a combination of experience, science
and engineering. In order to achieve a successful scale-up between the different phases, it is essential
that the Critical Material Attributes (CMAs) and Critical Quality Attributes (CQAs) of those materials
involved in the formulation of the product together with the Critical Process Parameters (CPPs) of the
manufacturing process are well defined since the beginning. Risk management tools can help controlling
the critical steps of the process.
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Risk assessment can be defined as the identification of hazards and the analysis and evaluation of risks
associated with exposure to those hazards. It is commonly understood that risk is the combination of
the probability of occurrence of harm and the severity of that harm, risk scenarios are the events that
identify the risks associated with the use of a system. The adoption of effective risk management is
indispensable to create awareness about the critical steps of the process with most probability to cause
failure, and how to control them.
Process mapping should be undertaken to ensure that all possible risks are considered, it is a map
performed by interdisciplinary teams which provides a better understanding of the process and assists
in providing a structured methodology for risk identification (failure modes identification). After identifying
the risk and its scenario, the effects are considered. The next stage is to determine the likelihood of an
adverse event to happen and assigning a value to that estimate. The parameters probability, severity
and detectability should be identified for each risk. Frequency of probability is rated from 1 to 3 in
accordance to its likelihood:
- Level 1 (low): the frequency of the event occurring is once per ten thousand transactions;
- Level 2 (medium): the frequency of the event occurring is once per thousand transactions;
- Level 3 (high): the frequency of the event occurring is once per hundred transactions.
Severity of the potential effect of the failure requires the team to consider which impact the event has
on the product quality or data integrity. The impact of the consequence is rated also from 1 to 3:
- Level 1 (low): expected to have a minor negative impact, the damage is not expected to have a
long term detrimental effect;
- Level 2 (medium): expected to have a moderate impact, the impact can be expected to have a
short to medium term detrimental effect;
- Level 3 (high): expected to have a very high significant negative impact, the impact can be
expected to have significant long-term effects and potentially catastrophic short term effects.
Having assigned the probability of the risk and the level of impact that such an event may have, the risk
can be classified. The risk is a multiplication of probability and severity. It can range from:
- Level 1 (high): the probability that this failure appears is high and that the impact on product
quality or data integrity is high or medium;
- Level 2 (medium): moderate impact on product quality or data integrity;
- Level 3 (low): practically no impact on product quality or data integrity.
The detectability stage is performed to identify if the risk can be recognized or detected by other means
in the system. The probability of a risk being detected is rated 1, 2 or 3 according to its detection
possibilities:
- Level 1 (high): a reliable detection device is continuously used on the system for direct
parameter measurement and leads to alarm activation or automatic system safe reconfiguration
in case of threshold overrunning (secured);
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- Level 2 (medium): a reliable detection procedure is systematically applied however it gives
delayed results, as another option an indirect measuring device can be used, or a direct
measuring device in line with no alarm (insufficient secured);
- Level 3 (low): no reliable detection device is used nor detection procedure as part of the system
operation or monitoring (not secured).
The risk evaluation can be done by the comparison against qualitative or quantitative criteria. Historical
data and trends should be evaluated. For quantitative evaluation, risks prioritization can be followed.
Risk priority number is a multiplication of three parameters taking into account the potential failure
associated with the potential effect and its detectability.
- High risk priority number: function or component is critical, validation measures are to be taken;
- Medium risk priority number: function or component is potentially critical, validation measures
are to be taken;
- Low risk priority number: function or component is not critical and there are no validation actions
or measures to be taken.
The risk management strategy has been completed and correctly applied as soon as the risk reduced
to an acceptable level and when the risk control process has been accepted. If the evaluation reached
to the conclusion that controls are not enough the risk reduction process should be evaluated. (ICH
2005)
Application of statistical methods such as Design Of Experiments (DOE) together with advances in
measurement tools such as PAT allow improvements in process understanding and control. DOE are a
mean to gain knowledge about the process and design an effective control strategy by allowing the
establishment of multivariate interactions between the variable inputs (material attributes and process
parameters for example) and the outputs (in-process material, intermediates or final product). It makes
it easier to apply risk management. PAT is an innovative mean of control that includes timely analysis
and control loops to adjust the processing conditions so that the output remains constant. Manufacturing
using this system can provide a higher degree of process control, reducing the risks. (FDA 2011)
These advances are expected to cause a shift from trial and error to rational process scale-up following
Quality by Design (QbD) initiative. QbD is a systematic approach to development that begins with
predefined objectives and emphasizes product/process understanding simultaneously with process
control, based on science and quality risk management. (ICH 2009)
The first studies performed to validate a product start at a laboratory scale, following the pilot batches
and finally the scale-up to production batches. (Gibson 2001)
Laboratory scale batches
These batches are produced at the research and early development laboratory stage, they have a very
small size, approximately one tenth of a normal production batch. The production of these batches is
15
helpful to support formulation and packaging development, clinical and pre-clinical studies. The data
that these batches provide are useful to define the products characteristics and enable the choice of
Batch failure 3 2 6 2 12 WFI is continuously sparged with filtered nitrogen throughout the
compounding. Oxygen sensor is calibrated before compounding.
F pH
measurement
and pH
adjustment
pH meter malfunction,
error in pH adjusting
solution quantity
Higher or lower pH
measurement result
Batch failure 3 2 6 1 6 pH meter is calibrated daily to cover the pH range on the MBR. pH adjustment
is performed with acid and basic solutions and checked by IPC pH meters
G Final QS Human error, scale
malfunction
Low or high assay Batch failure 3 1 3 2 6 Balance is calibrated and verified prior to each compounding, the step is
double verified. Final volume is verified with calibrated ruler.
H Filtration Product incompatibility
with filter membrane,
filter clogging
Low assay or high
impurity level
OOS results 3 1 3 1 3 The filter membrane used is the same as tested and validated at the R&D
site.
I Filling Improper nitrogen
headspace purging
Product degradation Batch failure 3 2 6 2 12 Oxygen headspace is monitored by IPC. The product is filled with nitrogen
flushing. The filling machine is qualified to meet product oxygen headspace.
specifications. Error in weights entry or
machine malfunction
Incorrect fill volume Low or high
assay, content
uniformity
affected
2 1 2 1 2 Filling start-up with volume verification by IPC. In-process control of fill volume
by IPC.
Washing machine, tunnel
or filling mal function
Product degradation Quality of the
batch
3 2 6 1 6 Critical holding time study, including the evaluation of the impact of 2 hours
line stoppage during filling.
J Protect product
from light
Human error, handling
instructions missing
Product degradation OOS results 3 2 6 1 6 The product was challenged under normal lights and did not significantly
impact the product quality for an exposure period up to 7 days.
K Inspection Product defects/particles Product degradation Batch failure 1 2 2 1 2 Inspection of the batches for particles. Samples are placed on stability.
A2
Annex B – Sampling scheme for product A
Figure 7 – Sampling scheme of product A manufacturing process
A3
Annex C – Risk management tools (FMEA) for product B
Table 13 – FMEA for product B
ID Process step Cause failure Potential effect Effect Severity Probability Criticality Detection SPD Control
A API calculations Added amount of
API is > or <
Low or high assay Batch failure 3 1 3 1 3 Calculation of the quantity of API is double verified before weighing.
B API handling Handling
instructions missing
API handling, low
or high assay
Batch failure 3 1 3 1 3 The weighing process is performed in a plastic bag.
C pH measurement
and adjustment
pH meter
malfunction, error
in pH adjusting
Higher or lower pH
measurement
result
pH OOS results,
product degradation
3 1 3 1 3 pH meter is calibrated daily to cover the pH range. pH adjustment is performed with
acid or basic solutions. Sample is checked by IPC pH meters.
D API dissolution Incorrect visual
evaluation
Low or high assay,
homogeneity of the
bulk solution
Batch failure 3 1 3 1 3 Dissolution of API is double verified. A minimum dissolution time is stated. A sample
from the bottom of the preparation tank is collected to verify API dissolution.
E Final QS Human error, scale
malfunction
Low or high assay Batch failure 3 1 3 2 6 Balance is calibrated and verified prior to each compounding. This step is double
verified.
F Filtration Product
incompatibility with
filter membrane,
filter clogging
Low assay, high
impurity level
Batch failure 3 1 3 1 3 Filter membranes to be used (0.2 µm) are the same as previously used in West-Ward
(Bedford). Filter validation reports are available.
G Filling Error in filling
weights entry or
machine
malfunction
Incorrect fill
volume;
Low or high
assay
2 1 2 1 2 Filling start-up with volume verification by IPC. In-process control of fill volume by IPC.
Washing machine,
tunnel or filling
machine,
malfunction leading
to line stoppages
Product
degradation
Compromise
quality of the
batch
3 2 6 1 6 The product is not oxygen or light sensitive. Maximum bulk hold time and the impact of
a 2 hours line stoppage is studied.
H Inspection Product defects;
colour or particles
Product
degradation or
process related
Batch failure 3 2 6 1 6 Inspection of the batches. Samples are placed on stability after inspection.
L Labelling and
Packaging
Uncontrolled
exposure to
ambient conditions
Product
degradation
Batch failure 3 1 3 1 3 The product is not light or heat sensitive, submission batches are labelled and packed
under normal lights to challenge the product.
A4
Annex D – Sampling scheme for product B
Figure 8 - Sampling scheme of product B manufacturing process
A5
Annex E - Risk assessment for the technology transfer of product B from Bedford to Hikma
Table 14 - Risk assessment for the technology transfer of product B from Bedford to Hikma regarding compounding
Item Current New Justification for change Risk Categorization
Batch size 80 L and 250 L 50L and 200 L As part of the technology
transfer to the new
manufacturing site. To
generate sufficient vials for
stability
Low
Compounding evaluated during submission
batches. Commercial sizes defined based on
market demand and during process validation.
Compounding
tank
75 gallons stainless
steel tank with a
propeller
100L or 200L stainless
steel
tank with a 4 blade
magnetic stirrer
As part of the Technology
Transfer to the new
manufacturing site
Low
Same material of construction (stainless
steel).
Compounding process evaluated during
submission batches manufacture.
Temperature
Mixing speed
and time
21-23ºC. 8-12 minutes
for excipient
dissolution, 178-182
minutes for API
dissolution. Mixing
speed: 550-600 rpm
20-25ºC (room
temperature). Average
mixing times and speeds
challenged on each step
As part of the Technology
Transfer to the new
manufacturing site
Low
Compounding process evaluated during
submission batches manufacture; New mixing
speeds/times evaluated to ensure efficient
mixing in the new tank without splashing and
without excessive foaming (if any).
API &
Excipients
API from Reliable.
Excipients from
Bedford suppliers
Same API supplier. Hikma
excipients suppliers
As part of the Technology
Transfer to the new
manufacturing site
Low
New mixing speeds/times evaluated during
submission to ensure efficient mixing
dynamics in the new tank without splashing
and without excessive foaming (if any).
A6
Table 15 - Risk assessment for the technology transfer of product B from Bedford to Hikma regarding filtration and filling
Item Current New Justification
for change
Risk categorization (low/medium/high)
Filtr
ati
on
Filtration
train
design
Two filters in parallel for
clarification and two
redundant filters used for
final filtration (0.2 µm)
One final filter inside the
sterile core (0.2 µm)
As part of the
technology
transfer to the
new
manufacturing
site
Low
Two filters in series inside the sterile core does not mean higher
sterility assurance. All the internal standard sterility assurance
controls are in place during submission. Same filter membrane
is used with the same porosity and from the same supplier. Less
extractables are expected by using one filter instead of two.
Fillin
g
Tubing Platinum cured silicone or
teflon
Teflon
Low
Teflon is considered as an inert material. Teflon has lower
extractables.
Automatic weighing is efficient. The filling machine is capable of
filling the product within the specified limit.
Fill volume consistency along the filling process is evaluated
during the manufacture of the submission batch. A proper
extended data compilation is performed during submission and
PV batches in order to evaluate the impact of each
manufacturing step on product quality, which includes extended
in-process analysis during filling in order to validate the entire
filling process and prove that it is not affecting the quality of the
product.
Fill
volume
Target fill weights are
checked every 15 minutes
gravimetrically using the
theoretical density to
ensure that vials are filled
correctly
Fill weight, based on
actual density. Filling line 5
has an automatic IPC.
Manual volume
verification is also
performed
IPC of
bulk
solution
Appearance, assay, pH,
density, osmolality and
bioburden were tested
before filtration
Bulk solution is tested
(before filtration). Routine
IPC tests are performed
(particles)
A7
Annex F – Risk assessment for the increase of product B batch size from submission scale to a proposed commercial
scale
Table 16 - Risk assessment for the scale-up to commercial size regarding the preparation tank, dissolution times, mixing speeds and filtration of product B
Item Submission batch sizes
(50L, 200L)
Proposed batch sizes
(380L, 1800L)
Rational/Risk evaluation
Preparation
tank
100L stainless steel tank.
200L stainless steel tank
600L stainless steel tank
2000L stainless steel tank
Low
Same material of construction (stainless steel).
Dissolution
times and
mixing
speeds
The minimum times were
challenged
The mixing times will be
challenged based on the data
collected on the submission
batches
Low
Typical mixing ranges for the selected tank will be used and evaluated
to assure proper dissolution/homogenization, having as indicative the
data collected during submission batches.
Filtration 0.2 µm PVDF filter
0.2 µm PVDF filter
Low
Same filter reference will be used.
Filter validation studies are available, covering the following
parameters: 16 hours as the maximum contact time of the product with
the filter, a maximum pressure of 2000 mbar and a maximum flow of
11.59 mL/min.cm2 of filter area.
Dead volume (which includes any filter adsorption) was evaluated and
conclusions are applicable to the new batch size.
Maximum contact of the
product with the filter: NA
Maximum contact of the product
with the filter: 16 hours
Filtration pressure ≤ 2.0 bar Filtration pressure ≤ 2.0 bar
A8
Table 17 - Risk assessment for the scale-up to commercial size regarding the filtration and actual production yield of product B
Item Submission batch sizes
(50L, 200L)
Proposed batch sizes
(380L, 1800L)
Rational/Risk evaluation
Filling
The filling duration was less than 2
hours (for both batches without
considering line stoppage
challenges)
The approximate filling
duration is between 4 hours
and 8 hours, assuming an
average filling speed for
each presentation
Maximum/minimum filling
speeds will be challenged
Low
The estimated filling times are well within the current maximum
qualified time for aseptic filling (26 hours 25 minutes) and well within
the maximum holding time between the start of API addition and the
end of filling (established as 72 hours at room temperature).
The 2 hours line stoppage was challenged and showed no impact on
the quality of the finished product.
The filling speed was 100% for both
batches (466 vials/minute for the
6 ml vials and 216 vials/minute for
the 30 mL vials)
Actual
production
yield
(based on
quantity for
stock and
total
samples)
77% – 91% *
Expected yield is ≤99% *
%991002000000
100002000000
ml
mlml
%98100500000
10000500000
ml
mlml
Not applicable
The manufacturing process yield limits will be established after
manufacture of at least 30 batches.
* Considering worst case fixed bulk/product losses for commercial batches of around 10L for residual volume in the filtration / filling system; for IPC (bulk testing
and samples during filling) and for finished product testing – and without considering rejected vials during inspection.