TECHNICAL ASPECTS RELATED TO THE MANUFACTURE

OF INJECTABLE PHARMACEUTICAL PRODUCTS –

FROM R&D TO PRODUCTION

Mafalda Filipa Machado Nunes

Thesis to obtain the Master of Science Degree in

Pharmaceutical Engineering

Supervisors:

Professor António José Leitão Neves Almeida

Professor José Monteiro Cardoso de Menezes

Examination Committee:

Chairperson: Professor João Carlos Moura Bordado

Supervisor: Professor António José Leitão Neves Almeida

Members of the Committee: Professora Helena Maria Cabral Marques

Dra. Ana Paula Gouveia Antunes Gageiro

December 2015

2

TECHNICAL ASPECTS RELATED TO THE MANUFACTURE

OF INJECTABLE PHARMACEUTICAL PRODUCTS –

FROM R&D TO PRODUCTION

Mafalda Filipa Machado Nunes

Thesis to obtain the Master of Science Degree in

Pharmaceutical Engineering

December 2015

3

ABSTRACT

The master thesis subject falls within the scope of the work developed in the Technical Services

department of Hikma Farmacêutica S.A. and its aim is to assess the technical aspects and activities

related to the transfer of an injectable pharmaceutical product from development phase to production.

After development of a new pharmaceutical product, several technical aspects need to be evaluated

and numerous validation activities need to be performed prior to start routine production and

commercialization. Technology transfer involves transfer of product and process knowledge to achieve

product realization and includes all the activities required for successful progress from pharmaceutical

development (R&D) to production (for new products) or from one manufacturing site to another (for

marketed products).

Process validation is part of technology transfer and is used to demonstrate that the manufacturing

process developed, operated within established parameters, can consistently deliver the intended

product. A proper correlation between process inputs, their associated manufacturing controls and

process outputs is crucial to successful process validation. Since there are several inputs, outputs and

controls associated with each manufacturing operation, a systematic approach that emphasizes product

and process understanding, based on quality risk management, is crucial to identify and to evaluate the

process validation activities to be performed during technology transfer.

Keywords: injectable products, technology transfer, process validation

4

RESUMO

O assunto da dissertação de mestrado insere-se no âmbito do trabalho desenvolvido no departamento

Technical Services da Hikma Farmacêutica S.A. e o seu objetivo é avaliar os aspetos técnicos e as

atividades relacionadas com a transferência de um produto farmacêutico injetável da fase de

desenvolvimento para a fase de produção. Após o desenvolvimento de um novo produto farmacêutico,

diversos aspetos técnicos precisam de ser avaliados e numerosas atividades de validação têm que ser

realizadas antes de se iniciar a produção de rotina e a comercialização. A transferência de tecnologia

envolve a transferência de conhecimentos acerca do produto e do processo, de modo a permitir a

obtenção do produto e inclui todas as atividades necessárias para progredir da fase de desenvolvimento

para a fase de produção (no caso de novos produtos) ou de um local de fabrico para outro (no caso de

produtos já existentes).

A validação de processo faz parte da transferência de tecnologia e tem como intuito demonstrar que o

processo de fabrico desenvolvido, executado de acordo com os parâmetros estabelecidos, pode

originar consistentemente o produto pretendido. Uma correlação adequada entre inputs do processo,

controlos associados e outputs é essencial para uma validação de processo bem-sucedida. Uma vez

que existem diversos inputs, outputs e controlos associados a cada operação de fabrico, uma

abordagem sistemática que enfatize a compreensão do produto e do processo, com base na gestão de

risco, é essencial para identificar e avaliar as atividades de validação que têm que ser realizadas

durante a transferência de tecnologia.

Palavras-chave: injetáveis, produto acabado, transferência de tecnologia, validação de processo

5

TABLE OF CONTENTS

LIST OF ABBREVIATIONS ..................................................................................................................... 6

LIST OF FIGURES .................................................................................................................................. 8

LIST OF TABLES .................................................................................................................................... 9

1. INTRODUCTION ............................................................................................................................... 10

2. INJECTABLE PHARMACEUTICAL PRODUCTS ............................................................................. 11

3. PROCESS VALIDATION................................................................................................................... 23

4. RELATIONSHIP BETWEEN PROCESS VALIDATION, QUALITY RISK MANAGEMENT AND

PHARMACEUTICAL QUALITY SYSTEM ............................................................................................. 30

5. TECHNOLOGY TRANSFER ............................................................................................................. 38

6. CONCLUSION ................................................................................................................................... 73

7. FUTURE PERSPECTIVES ............................................................................................................... 74

8. REFERENCES .................................................................................................................................. 75

9. APPENDICES ................................................................................................................................... 79

6

LIST OF ABBREVIATIONS

API – Active Pharmaceutical Ingredient

ATCC – American Type Culture Collection

CAPA – Corrective and Preventive Actions

CCS – Container Closure System

CFU – Colony Forming Unit

CGMP – Current Good Manufacturing Practice

CMA – Critical Material Attribute

COA – Certificate of Analysis

CPP – Critical Process Parameter

CQA – Critical Quality Attribute

DOE – Design of Experiments

EFA – Effective Filtration Area

EP – European Pharmacopoeia

ETFE – Ethylene Tetrafluoroethylene

FDA – Food and Drug Administration

HDPE – High Density Polyethylene

HEPA – High-Efficiency Particulate Air

ICH – International Conference on Harmonization

IOQ – Installation/Operational Qualification

IPC – In-Process Control

IQ – Installation Qualification

ISO – International Organization for Standardization

MSDS – Material Safety Data Sheet

OOS – Out of Specification

OOT – Out of Trend

OQ – Operational Qualification

PAT – Process Analytical Technology

PNSU – Probability of a Non-Sterile Unit (also known as SAL)

PP – Polypropylene

7

PPQ – Process Performance Qualification

PTFE – Polytetrafluoroethylene

PVDF – Polyvinylidene Fluoride

QTPP – Quality Target Product Profile

R&D – Research and Development

RH – Relative Humidity

RLD – Reference Listed Drug

RPN – Risk Priority Number

RTS (or RS) – Ready-to-Sterilize

RTU (or RU) – Ready-to-Use

SAL – Sterility Assurance Level (also known as PNSU)

USP – United States Pharmacopeia

WFI – Water for Injection

8

LIST OF FIGURES

Figure 1 – General steps involved in the manufacture of injectable drug products .............................. 15

Figure 2 – Pharmaceutical lyophilizer / freeze-dryer ............................................................................ 16

Figure 3 – Steps involved in the manufacture of a lyophilized drug product ......................................... 17

Figure 4 – Example of a label of a liquid product .................................................................................. 18

Figure 5 – Example of a label of a lyophilized product .......................................................................... 19

Figure 6 – Clear and amber glass vials ................................................................................................. 20

Figure 7 – Rubber stoppers ................................................................................................................... 20

Figure 8 – Aluminum seals with different styles and colors .................................................................. 20

Figure 9 – Rubber stopper styles .......................................................................................................... 21

Figure 10 – Aluminum seal styles ......................................................................................................... 21

Figure 11 – Schematic relationship between inputs (CMAs and CPPs) ............................................... 25

Figure 12 – Overview of a general quality risk management process .................................................. 32

Figure 13 – Template of a Cause and Effect Diagram .......................................................................... 35

Figure 14 – Stainless steel tank ............................................................................................................ 51

Figure 15 – Capsule filter ...................................................................................................................... 54

Figure 16 – Cartridge filter and stainless steel housings ...................................................................... 54

Figure 17 – Eight elements of a sterile filtration validation .................................................................... 54

Figure 18 – Appearance of a parenteral product before and after lyophilization .................................. 60

9

LIST OF TABLES

Table 1 – Clean area air classification (particles/m3) ............................................................................ 13

Table 2 – Advantages and disadvantages of lyophilization process ..................................................... 16

Table 3 – Stages of a product lifecycle, goals and associated technical activities ............................... 30

Table 4 – Example of drug product release specifications for a liquid injectable product .................... 40

Table 5 – Example of drug product release specifications for a lyophilized injectable product ............ 40

Table 6 – Typical borosilicate glass composition .................................................................................. 45

Table 7 – Example of a lyophilization cycle for an injectable product ................................................... 60

Table 8 – Example of a schematic approach for presenting a rationale for submission of a proposed

scale-up batch size of a specific product in a specific filling line ........................................................... 67

Table 9 – Stability storage conditions and study duration per type of stability study ............................ 69

Table 10 – Climatic zones ..................................................................................................................... 69

Table 11 – Stability storage conditions (general case) ......................................................................... 70

Table 12 – Stability storage conditions (drug products stored in semi-permeable containers) ............ 71

Table 13 – Stability storage conditions (drug products intended for storage in a refrigerator) ............. 72

Table 14 – Stability storage conditions (drug products intended for storage in a freezer) .................... 72

10

1. INTRODUCTION

After development of a new pharmaceutical product, several technical aspects need to be evaluated

and numerous validation activities need to be performed prior to start routine production and

commercialization. Technology transfer involves transfer of product and process knowledge to achieve

product realization and includes all the activities required for successful progress from pharmaceutical

development (R&D) to production. Additionally, technology transfer is also applicable for marketed

products and involves transfer of processes from one manufacturing site to another.

The aim of pharmaceutical development is to develop a product suitable for its intended use, using a

defined manufacturing process, which should be robust and reproducible in order to deliver consistently

a product with the desired quality.

The data obtained and the knowledge gained from the pharmaceutical development studies and

manufacturing experience during the R&D phase, provide evidence to support the establishment of the

design space, specifications and manufacturing controls / critical process inputs. The intention is to build

quality into the pharmaceutical product while it is still in the research and development phase, to make

sure that the final product is going to meet the requirements prior to entering the production phase.

Critical process inputs, i.e., critical material attributes (CMAs) and critical process parameters (CPPs),

should be identified through a risk-based approach since they represent sources of variation that affect

the product quality. Once these parameters are identified, they should be controlled commensurate with

the risk they represent to the product quality by implementing the proper control strategies.

Process validation is part of technology transfer and is used to demonstrate that the manufacturing

process developed, operated within established parameters, can consistently deliver the intended

product. The evidence obtained from process validation activities proves to the competent authorities

that the manufacturing process is under control and that the product obtained has the desired quality.

Therefore, after approval, it can start to be routinely produced for commercial purposes, with confidence.

Nevertheless, it is important to recognize that process validation is not an isolated event and should

occur throughout the lifecycle of the product.

An overview regarding injectable pharmaceutical products is presented in the next chapter while the

following chapters focus mainly on process validation, quality risk management and technology transfer

regarding the manufacture of parenteral products.

11

2. INJECTABLE PHARMACEUTICAL PRODUCTS

According to USP Chapter <1>, “Parenteral articles are preparations intended for injection through the

skin or other external boundary tissue, rather than through the alimentary canal, so that the active

substances they contain are administered, using gravity or force, directly into a blood vessel, organ,

tissue, or lesion”. Parenteral or injectable pharmaceutical products are prepared by methods designed

to ensure that they meet Pharmacopeial requirements for sterility, pyrogens, particulate matter and other

contaminants. An Injection is a preparation intended for parenteral administration and/or for constituting

or diluting a parenteral article prior to administration. [1]

2.1. Nomenclature and definitions

The preparations intended for parenteral administration are available either as liquid (solutions,

emulsions or suspensions) or solid products. According to USP Chapter <1>, the following nomenclature

can be used to classify these types of preparations: [1]

[DRUG] Injection – Liquid preparations that are drug substances or solutions thereof.

[DRUG] for Injection – Dry solids that, upon the addition of suitable vehicles, yield solutions

conforming in all respects to the requirements for Injections.

[DRUG] Injectable Emulsion – Liquid preparations of drug substances dissolved or dispersed in

a suitable emulsion medium.

[DRUG] Injectable Suspension – Liquid preparations of solids suspended in a suitable liquid

medium.

[DRUG] for Injectable Suspension – Dry solids that, upon the addition of suitable vehicles, yield

preparations conforming in all respects to the requirements for Injectable Suspensions.

2.2. Raw materials

Preparations intended for parenteral administration contain one or more drug substances, also known

as active pharmaceutical ingredients (API). Additionally, these preparations may contain appropriate

excipients (vehicles and/or other substances).

2.2.1. Vehicles

Aqueous Vehicles – Water for Injection (WFI) is the most common vehicle used for aqueous

parenteral preparations. WFI is water purified by distillation or other purification process equivalent or

superior to distillation in the removal of chemicals and microorganisms. It contains no added substances

and a bacterial endotoxin content less than 0.25 USP Endotoxin Unit/mL. It is intended for use in the

preparation of parenteral solutions and not for direct parenteral administration. [1] [2] [3]

12

Other Vehicles – Oils used as vehicles for non-aqueous injections are of vegetable origin, are

odorless or almost odorless and have no odor suggesting rancidity. Synthetic mono- or diglycerides of

fatty acids and other non-aqueous vehicles may be used as vehicles, provided they are safe and do not

interfere with the therapeutic efficacy of the preparation or with its response to the specified assays and

tests. [1] [3]

2.2.2. Added Substances

Suitable substances may be added to preparations intended for injection, provided they are safe in the

amounts administered and do not interfere with the therapeutic efficacy or with the responses to the

specified assays and tests. For instance, sufficient amounts of Sodium Chloride may be added in order

to obtain an isotonic solution. Some substances, such as coloring agents, may be avoided and should

not be added only for the purpose of coloring the finished preparation. Special attention may be given

when using added substances for preparations that are administered in a volume higher than 5 mL.

Preparations intended for injection that are packaged in single-dose containers do not require the use

of antimicrobial agents. On the other hand, a suitable substance or mixture of substances to prevent the

growth of microorganisms must be added to preparations intended for injection that are packaged in

multiple-dose containers, unless when the substance contains a radionuclide with a physical half-life of

less than 24 hours or when the active ingredients have themselves antimicrobial activity. [1] [3]

2.3. Manufacturing process

The manufacture of pharmaceutical drug products should meet the requirements of current Good

Manufacturing Practices (cGMPs), which are guidelines to provide assurance of proper design,

monitoring and control of manufacturing processes and facilities. Adherence to the cGMP regulations

assures the identity, strength, quality and purity of drug products by requiring that its manufacturers

adequately control each manufacturing operation. This includes establishing strong quality management

systems, obtaining appropriate quality raw materials, establishing robust operating procedures,

detecting and investigating product quality deviations and maintaining reliable testing laboratories. It

helps to prevent the occurrence of contaminations, mix-ups, deviations and failures and assures that

the drug products manufactured meet their quality standards. [3] [4] [5]

The cGMPs are minimum requirements and are flexible in order to allow each manufacturer to decide

individually how to best implement the necessary controls by using appropriate design, processing

methods and testing procedures. The flexibility in these regulations allows companies to use modern

technologies and innovative approaches to achieve higher quality through continual improvement.

Accordingly, the "c" in cGMP stands for "current," requiring companies to use technologies and systems

that are up-to-date in order to comply with the regulations. [3] [4] [5]

13

The cGMPs require testing but testing alone is not adequate to ensure quality, since it is usually done

on a small sample of a batch. Therefore, it is important that drug products are manufactured under

conditions and practices required by the cGMP regulations to assure that quality is built into the design

and manufacturing process at every step. The safety and efficacy of drug products can be more easily

achieved if their manufacture occurs at facilities that are in good condition, with equipment that is

properly maintained and calibrated, by employees who are qualified and fully trained and following

processes that are reliable and reproducible. [3] [4] [5]

The manufacture of injectable products should occur in clean areas, which should be maintained to an

appropriate cleanliness standard (refer to table 1) and supplied with air which has passed through filters

of an appropriate efficiency (HEPA filters). Injectable products are mandatorily sterile and sterility

assurance can be achieved by validation and control of each manufacturing process step, environmental

monitoring / control, maintenance of HEPA filter integrity and maintenance of a differential pressure (of

10 – 15 Pa) between areas of differing class. [3] [4] [6] [7] [8] [9]

Table 1 – Clean area air classification (particles/m3). Adapted from [7]

Particle size ISO 14644-1 United States FDA Guidance

and USP <1116> European Union Annex 1

ISO 5 ISO 5 / Class 100 Grade A

Grade B (at rest)

≥ 0.5 µm 3520 3520 3520

≥ 5 µm 29 Not specified 20 (Grade A) /

29 (Grade B, at rest)

ISO 6 ISO 6 / Class 1000 N/A

≥ 0.5 µm 35200 35200 N/A

≥ 5 µm 290 Not specified N/A

ISO 7 ISO 7 / Class 10000 Grade B (in operation)

Grade C (at rest)

≥ 0.5 µm 352000 352000 352000

≥ 5 µm 2900 Not specified 2900

ISO 8 ISO 8 / Class 100000 Grade C (in operation)

Grade D (at rest)

≥ 0.5 µm 3520000 3520000 3520000

≥ 5 µm 29000 Not specified 29000

An environmental monitoring program should be implemented in order to maintain the clean areas to an

appropriate cleanliness level. The most commonly accepted international cleanroom standard is ISO

14644-1 [9]. ISO class designations are based on the number of particles greater than a specified size

(0.1 – 5 µm) per cubic meter of air sampled. ISO 14644-1 defines classes from 1 to 9 (with ISO 1 being

the cleanest) but only ISO classes 5 to 8 are used in the pharmaceutical industry for the manufacture of

sterile products. For the United States, the FDA’s 2004 Guidance for Industry [4] and USP General

Chapter <1116> [8] include ISO classes 5 – 8 and their corresponding Federal Standard 209E classes

14

(although this classification is obsolete, it is still mentioned for continuity), only for particles ≥ 0.5 µm.

The European Union use an alphabetic classification of Grades A to D (according to EU Guidelines to

Good Manufacturing Practice Annex 1 [6]). For each grade, a ≥ 0.5 µm and ≥ 5 µm particle count is

specified, for both at rest and in operation states. Each grade has up to two corresponding ISO classes,

as follows:

Grade A – ISO 4.8 at rest and in operation, based on the reduced maximum count of particles

≥ 5 µm per cubic meter from 29 (ISO 5) to 20 (ISO 4.8);

Grade B – ISO 5 at rest, ISO 7 in operation;

Grade C – ISO 7 at rest, ISO 8 in operation;

Grade D – ISO 8 at rest, undefined in operation.

Sterile products can be manufactured by two different methods: aseptic processing or terminal

sterilization. These products should be manufactured using aseptic processing only when terminal

sterilization is not feasible. Therefore, when designing the manufacturing process of a sterile drug

product, the first approach should be evaluating if the product can be terminally sterilized. When aseptic

processing is selected over terminal sterilization, proper scientific justification should be provided in the

marketing authorization dossier. The most common and plausible reason is the degradation of the drug

substance and/or drug product when exposed to terminal sterilization conditions. A decision tree for

sterilization choices for aqueous products is presented in Appendix 1. [3] [4] [6] [10]

2.3.1. Terminal sterilization

Terminal sterilization usually involves performing the filling and closing processes under high-quality

environmental conditions (aseptic conditions are not required), in order to minimize microbial and other

particulate content in the product and to help ensuring that the subsequent sterilization process is

successful. Therefore, the product and the container closure system must have low bioburden but are

not sterile. The product in its final container is then subjected to a terminal sterilization process such as

heat or irradiation. The method of choice for aqueous preparations is moist heat sterilization (in an

autoclave) and, therefore, it should be used whenever possible. [3] [4] [6]

2.3.2. Aseptic processing

In aseptic processing, the product and the container closure system are previously subjected to

sterilization methods separately. Since the product is not sterilized in its final container, it is required that

the filling and closing processes occur under aseptic conditions and following aseptic technique. Usually,

different sterilization methods are applied to the individual components of the final product. Glass

containers are subjected to dry heat sterilization (in a depyrogenation tunnel), rubber closures are

subjected to moist heat sterilization (in an autoclave) or purchased irradiated (pre-sterilized) and liquid

dosage forms are subjected to sterilizing filtration (through a sterilizing-grade filter). Each one of these

manufacturing steps should be properly validated and controlled. Any manipulation of the sterilized

components poses the risk of contamination and, therefore, appropriate controls should be in place, in

order to avoid obtaining a non-sterile product. [3] [4] [6]

15

Figure 1 summarizes the steps involved in the manufacture of terminally sterilized products and

aseptically processed products.

Terminally sterilized products Aseptically processed products

Figure 1 – General steps involved in the manufacture of injectable drug products

(terminally sterilized vs. aseptically processed products)

Some aseptically processed products are subjected to an additional manufacturing operation known as

lyophilization or freeze-drying. Lyophilization is a process in which water is removed from an aqueous

liquid product after it is frozen and placed under a vacuum, allowing the ice to change directly from solid

to vapor without passing through a liquid phase. The process is performed at low pressure and

temperature (which makes it suitable for thermolabile products) and consists mainly of the following

three separate and interdependent phases: [3] [4] [11]

Freezing (ice nucleation) – solidification of water in order to obtain a product with the desired

crystalline structure;

Primary drying (sublimation phase) – removal of water by sublimation of ice;

Secondary drying (desorption phase) – desorption of unfrozen water in order to eliminate the

residual water remaining after primary drying.

Preparation of the bulk solution (compounding)

[under Grade C or D environment]

Filtration for bioburden reduction

[under Grade A environment (with at least Grade C background) or Grade C environment]

Filling / closing

[under Grade A environment (with at least Grade C background) or Grade C environment]

Terminal sterilization

Inspection, labelling and packaging

Preparation of the bulk solution (compounding)

[under Grade C environment]

Sterile filtration

[under Grade A environment (with Grade B background)]

Aseptic filling / closing

[under Grade A environment (with Grade

B background)]

Lyophilization

[under Grade A environment (with Grade

B background)]

Inspection, labelling and packaging

Closing

[under Grade A environment (with Grade

B background)]

Aseptic filling

[under Grade A environment (with Grade

B background)]

.

16

This process is usually applied to products that are instable in the liquid form and, therefore, are

preferably supplied in the solid form. It allows to improve the stability of these products and to increase

their shelf-life. Main advantages and disadvantages of lyophilization are mentioned in table 2. [3] [4]

[11]

Table 2 – Advantages and disadvantages of lyophilization process

Advantages

Enhanced product stability in a dry state

Removal of water without excessive heating of the product

Rapid and easy dissolution of reconstituted product

Disadvantages

Increased handling and processing time

Need for sterile diluent upon reconstitution

Cost and complexity of equipment

The lyophilization process occurs in a lyophilizer or freeze-dryer (refer to figure 2). The main

components of a lyophilizer are the following: [12]

chamber (with a variable number of shelves, where the product is placed to undergo the freeze-

drying process);

condenser (a chilled surface which collects the vapor that is being generated during the process

by condensation);

vacuum pump (to reduce the pressure inside the chamber).

Figure 2 – Pharmaceutical lyophilizer / freeze-dryer [12]

17

The manufacture of a lyophilized pharmaceutical dosage form involves several steps. Figure 3

summarizes the steps involved in the manufacture of a lyophilized product, supplied in vials. [3] [11] [12]

Figure 3 – Steps involved in the manufacture of a lyophilized drug product

Preparation of the bulk solution: Dissolving the drug substance and excipients in a suitable solvent, generally water for injection (WFI).

Sterilizing filtration: Sterilizing the bulk solution by passing it through a 0.2 µm bacteria-retentive filter.

Aseptic filling: Filling into individual sterile vials and partially stoppering the vials under aseptic conditions.

Loading: Placing the partially stoppered vials on temperature-controlled shelves inside the lyophilizer chamber under

aseptic conditions.

Freezing: Freezing the solution (transformation of most of the water into ice) by cooling the shelves.

Primary drying: Applying vacuum to the chamber and then raising the temperature of the shelves to sublimate the water from

the frozen state.

Stoppering: Complete stoppering of the vials by stoppering mechanisms installed in the lyophilizer.

Unloading: Collecting the fully stoppered vials from the lyophilizer.

Secondary drying: Heating the shelves (maintaining the chamber under vacuum) to remove traces of water remaining due to

adsorption.

Capping: Sealing the vials in a capping machine.

Inspection, labelling and packaging.

18

2.4. Labelling

The term labelling corresponds to all labels and other written, printed or graphic items (e.g., insert) on

an article's primary packaging container or on and in any package or wrapper in which it is enclosed

(except any outer shipping container). The term label designates that part of the labelling on the primary

packaging container. [1] [3] [13]

The label and the labelling usually mention the following information:

Name of the product;

In the case of liquid products, the percentage or amount of each drug substance in a specified

volume;

In the case of a dry powder or other product to which a diluent is intended to be added prior to

use, the amount of each drug substance, the final volume of solution or suspension, instructions

for proper storage of the constituted solution, and an expiration or beyond-use date limiting the

period during which the constituted solution may be administered;

Route (or routes) of administration;

Name and proportion of all excipients (except those added to adjust the pH or to make the drug

isotonic, which may be declared by name with a statement of their effect);

Storage conditions;

Name and place of business of the manufacturer, packer, or distributor;

Expiration date;

Lot number;

“Rx only” which means that the drug product is a prescription drug;

Recommended or usual dosage.

The label should not cover the whole length or circumference of the container, which should be labeled

so that a sufficient area remains uncovered to allow visual inspection of the contents.

Figures 4 and 5 illustrate two labels, one for a liquid product and another for a lyophilized product.

Figure 4 – Example of a label of a liquid product

[DRUG] INJECTION

19

Figure 5 – Example of a label of a lyophilized product

2.5. Packaging

A container closure system (or packaging system) refers to the sum of packaging components that

together contains and protect the dosage form. A primary packaging component is a packaging

component that is in direct contact with the dosage form, while a secondary packaging component is a

packaging component that is not in direct contact with the dosage form. [3] [14]

The selection of the container closure system is more critical for a liquid-base dosage form than for a

solid, since the liquids are more likely to interact with the packaging components. Nevertheless, each

drug product (either solid or liquid) should be packaged in an appropriate container closure system,

which should be suitable for its intended use. Suitability means that the packaging system complies with

the following criteria: [3] [14]

Protection: provides the dosage form with adequate protection from factors that can cause its

degradation throughout the shelf-life, such as, exposure to light, exposure to oxygen, loss of

solvent, absorption of water vapor and microbial contamination;

Compatibility: is compatible (i.e., does not interact) with the dosage form;

Safety: is composed of materials that are considered safe for use with the dosage form and the

route of administration;

Performance: is functional and allows a proper delivery of the drug product.

2.5.1. Primary packaging components

Since the primary packaging components are intended to be in direct contact with the dosage form,

special attention should be given to their materials of construction.

2.5.1.1. Containers

Parenteral preparations are usually supplied in the following containers: vials, ampoules, bags, bottles

and syringes. These containers are commonly made from glass (clear or amber type I glass) or plastic

[DRUG]

20

(e.g., HDPE and PP). The material of construction must be compatible with the drug product formulation

and should allow the visual inspection of the contents.

Glass vials are the main containers for injectable pharmaceutical products (refer to figure 6), due to

their high chemical resistance, impermeability to gases, temperature resistance and ease of cleaning

and sterilization. Their capacity usually ranges from 1 mL to 100 mL and they usually have a neck

diameter of 13 mm, 20 mm or 32 mm. [3] [14] [15] [16]

Figure 6 – Clear and amber glass vials [16]

2.5.1.2. Closures

Closures for parenteral preparations must fit the container properly, in order to preserve the quality of

the product and this combination should be validated to prove container/closure integrity. The more

common closures are rubber stoppers (refer to figure 7), which are usually accompanied with aluminum

seals (refer to figure 8). [3] [14] [17] [18]

Figure 7 – Rubber stoppers [18]

Figure 8 – Aluminum seals with different styles and colors [18]

Stoppers are typically made of elastomeric materials (such as, bromobutyl and chlorobutyl rubber) and

are available in different sizes and styles, according to the type of container they are intended for (refer

to figure 9). Several types of coating can be applied to the top and/or bottom surface of the stoppers.

Coating with fluorinated polymers (e.g., PTFE and ETFE) is widely used to reduce the risk of chemical

interactions between the closure and the drug product (i.e., to improve compatibility) but applying coating

to stoppers can provide many other advantages, such as: [3] [14] [17] [18] [19]

Lower level of extractables from the rubber;

Reduced particulate matter (visible and sub-visible particles);

Enhanced machinability, which usually leads to increased line speeds.

21

Figure 9 – Rubber stopper styles [18]

Aluminum seals are used in conjunction with stoppers to provide a secure closure for the containers

(e.g., vials). Aluminum seals are available in a wide range of styles and colors for easy product

identification (refer to figure 10). [3] [14] [18]

Figure 10 – Aluminum seal styles [18]

22

2.5.2. Secondary packaging components

Common secondary packaging components are overwraps and cartons, which generally have one or

more of the following functions: [3] [14]

Avoids excessive transmission of moisture or solvents into or out of the packaging system;

Provides protection from excessive transmission of gases (atmospheric oxygen, inert

headspace filler gas or other organic vapors) into or out of the packaging system;

Provides light protection for the packaging system (extremely important in the case of drug

products that are sensitive to light and are filled in clear containers);

Provides protection for a packaging system that is flexible or needs extra protection from rough

handling.

For instance, overwraps are usually used with bags, in order to avoid solvent loss, to protect the flexible

packaging system from rough handling and to provide light protection (in the case of drug products

sensitive to light). Cartons are more commonly used with vials, ampoules and syringes. Labels and

leaflets (inserts) are also considered secondary packaging components.

Since secondary packaging components are not intended to directly contact with the dosage form, there

is usually less concern regarding the materials from which they are made. Nevertheless, if the packaging

system is relatively permeable, there is a possibility that the dosage form could be contaminated by the

migration of an ink, adhesive component or from a volatile substance present in the secondary

packaging component. In these cases, the secondary packaging component should be considered a

potential source of contamination and the safety of its materials of construction should be taken into

consideration. [3] [14]

23

3. PROCESS VALIDATION

Process validation is part of technology transfer and is used to demonstrate that the manufacturing

process developed by R&D and transferred to industrial scale, operated within established parameters,

can consistently yield a product meeting its specified quality attributes. It is important however to

recognize that process validation is not an isolated event. A lifecycle approach should be applied in

order to link product and process development, validation of the commercial manufacturing process and

maintenance of the process in a state of control throughout routine production. [3] [20] [21]

Process validation includes several activities occurring throughout the lifecycle of the product, which

can be divided in three stages: [3] [20] [21]

Process Design: The manufacturing process intended for commercial production is defined

based on knowledge gained during pharmaceutical development.

Process Qualification: The process design is evaluated in order to determine the reproducibility

and robustness of the process.

Continued Process Verification: Assurance that the process remains in a state of control during

routine production.

All data gathered during process validation should be properly evaluated, which allows to understand

the process and to establish the appropriate strategy control that lead to adequate quality assurance.

Any source of variation should be studied and controlled in a manner commensurate with the risk it

represents to the process and, ultimately, to the product. [3] [20] [21]

Process validation includes not only initial validation of new products / processes but also subsequent

validation of modified processes and re-validation (scale-up or scale-down, for instance). Change in the

product / process should be evaluated through change control and may be followed by additional process

validation activities. [3] [20] [21]

The validation should cover all product presentations / strengths used for production of the drug product.

A matrix approach may be acceptable in certain circumstances, for instance, for products that have three

or more presentations (with the same bulk formulation but with different fill volumes). In these cases,

bracketing can be applied by fully evaluating the worst case presentations using a clear rationale. [3] [20]

[21]

3.1. Process Design

The aim of this stage is to design a process suitable for routine commercial production capable of

consistently delivering a product with the desired quality.

24

3.1.1. Product and Process Knowledge and Understanding [3] [20] [21] [22] [23]

The data gathered during product development activities provide valuable information and should be

considered to the process design stage. The Quality Target Product Profile (QTPP) is related to clinical

safety and efficacy of the drug product and is the basis for pharmaceutical product and process

development and optimization. It may include the following:

Intended use;

Intended dosage form;

Intended route of administration;

Dosage strength;

Container closure system;

Bioequivalence to the RLD in the case of generic products;

Expected CQAs (the QTPP is used as a starting point to establish the final CQAs).

According to ICH Guideline Q8(R2), “A CQA is a physical, chemical, biological or microbiological

property or characteristic that should be within an appropriate limit, range or distribution to ensure the

desired product quality”. CQAs are attributes considered critical for the efficacy and safety of the product

and, therefore, need to be controlled to ensure product quality. Different CQAs can be identified for each

type of pharmaceutical product. For injectable products, special attention should be paid to sterility and

bacterial endotoxins content. Other typical CQAs for liquid injectable products are appearance, assay,

impurities profile, pH and particulate matter (visible and sub-visible particles). For lyophilized products,

time of reconstitution and water content are also considered CQAs.

The characteristics of the equipment to be used for commercial production and the inputs expected to

cause variability in the production setting (such as, different component lots, production operators,

environmental conditions and measurement systems) should also be considered in the process design.

However, since the causes of variability of commercial production are not generally known at this stage,

laboratory or pilot-scale models designed to be representative of the commercial process are usually

used to estimate variability.

The following activities can help to obtain process knowledge and understanding which is crucial to

design an efficient process with an effective process control strategy:

Design of Experiments (DOE) – DOE studies are useful to gain process knowledge by revealing

relationships between the variable inputs (e.g., material attributes or process parameters) and

the resulting outputs (e.g., in-process material, intermediates or finished product) (refer to

figure 11). The results of DOE studies can provide a rationale to determine the design space,

by establishing ranges of incoming component quality, equipment parameters and in-process

material quality attributes. Risk analysis tools can be used to screen potential variables for DOE

studies in order to minimize the total number of experiments performed and increase the

knowledge gained.

25

Experiments or demonstrations at laboratory or pilot scale – activities conducted at small-scale

contribute to the evaluation of certain conditions and prediction of performance of the

commercial process.

Computer-based or virtual simulations of certain unit operations – computer modelling can also

provide process understanding and help avoiding problems at commercial scale.

Figure 11 – Schematic relationship between inputs (CMAs and CPPs)

and outputs (CQAs) for a pharmaceutical unit operation

All activities and studies resulting in process knowledge and understanding should be properly

documented, since documentation reflect the basis for decisions made about the process. This

information is useful during the following process validation stages (process qualification and continued

process verification), including when the design or the control strategy are revised.

3.1.2. Process Control Strategy [3] [20] [21] [22]

Process knowledge and understanding is the basis for establishing an appropriate process control

strategy for each unit operation and the whole process. Nevertheless, process controls can be improved

as process experience is gained.

Strategies for process control should focus on variability to assure product quality and can be designed

to reduce input variation, adjust for input variation during manufacturing (reducing its impact on the

output) or combine both approaches. Controls should include analysis of incoming materials, in-process

control and equipment monitoring at significant processing points.

Process analytical technology (PAT) is an advanced strategy that can be used to provide a higher

degree of process control and allow better process understanding. It includes timely in-process

measurements that allow immediate adjustment of the processing conditions in order for the output to

remain constant.

Output

materials /

product

Input

materials

Pharmaceutical Unit Operation

CPPs

CMAs CQAs

CQAs = f (CMA1, CMA2, …CPP1, CPP2, …)

26

3.2. Process Qualification

The aim of process qualification is to evaluate the process design in order to determine if it is capable

of consistent commercial production. This stage, which has to be successfully completed before

commercial distribution of the product, has two elements: [3] [20] [21] [24]

1. qualification of the equipment and utilities (such as water, steam and gases);

2. process performance qualification (PPQ).

3.2.1. Qualification of Utilities and Equipment [3] [20] [21] [24] [25]

Qualification of utilities and equipment refers to activities performed to demonstrate that they are suitable

for their intended use and perform properly. It includes the following activities:

Selection of utilities and equipment construction materials, operating principles and

performance characteristics.

Installation Qualification (IQ) – Verification that utility systems and equipment are built and

installed in compliance with the design specifications (i.e., built as designed with proper

materials, capacity and functions; properly connected and calibrated).

Operational Qualification (OQ) – Verification that utility systems and equipment operate in

accordance with the process requirements in all expected operating ranges. This should include

challenging the equipment or system functions comparable to that expected during routine

production and should also include the performance of interventions, stoppages and start-up as

is expected during routine production.

OQ normally follows IQ however, it may be performed as a combined Installation/Operational

Qualification (IOQ).

3.2.2. Process Performance Qualification [3] [20] [21] [24] [25]

The aim of process performance qualification (PPQ) is to confirm the process design and demonstrate

that the manufacturing process intended for commercial production consistently performs as expected.

As mentioned above, utilities and equipment should have been previously qualified. The manufacturing

process and control strategy should have been established in order to produce the PPQ batches (which

usually corresponds to the first commercial-scale batches of the drug product).

Successful PPQ should be completed prior to commercial distribution of the drug product. All data

gathered from commercial-scale batches and also from laboratory and pilot-scale studies is used to

support the decision of beginning commercial distribution. Additionally, previous credible experience

with sufficiently similar products and processes can be helpful.

Usually, PPQ has a higher level of sampling, additional testing and greater evaluation of process

performance than during routine commercial production, in order to confirm uniformity intra- and inter-

batch. The increased level of scrutiny, testing and sampling is used to establish appropriate levels and

27

frequency of routine sampling and monitoring, taking into consideration volume of production, process

complexity, level of process understanding and experience with similar products and processes.

PAT may ease the PPQ approach due to the real-time measurement of in-process material attributes,

which allow adjusting the process in a timely control loop in order to maintain the desired quality of the

output. Nevertheless, the goal of process validation (particularly, PPQ) is always the same, i.e., to

establish scientific evidence that the process is reproducible and will consistently deliver products with

the desired quality.

3.2.2.1. PPQ documentation

The main documents for this stage of process validation are a PPQ protocol and a subsequent PPQ

report. A Master Batch Record, describing all the steps to be followed during the manufacture of the

PPQ batches, is also an essential document and must be approved before production.

The PPQ protocol is a written document that specifies the manufacturing formula and conditions,

controls, testing and expected results. It should include mainly the following elements:

Manufacturing formula and batch size;

Production line and equipment involved, including compounding tanks;

Manufacturing conditions (including operating parameters, processing limits and components);

Critical process parameters;

Risk assessment and process validation approach;

Data to be collected and evaluated;

Tests to be performed and related acceptance criteria (for in-process control and finished

product release);

Sampling plan (including sampling points, number of samples and frequency of sampling for

each production step and quality attribute). The sampling plan should be adequate to provide

enough statistical confidence of quality both within a batch and between batches. Sampling

during this stage should be more extensive than during routine production, in order to gather

the maximum information and to gain the maximum understanding as possible;

Status of the validation of the analytical methods used for in-process and finished product

testing.

The PPQ protocol should also include criteria and process performance indicators that allow for a

scientific- and risk-based decision about the ability of the process to consistently produce the product

with the desired quality. The criteria should include:

a description of the statistical methods to be used in analyzing all collected data (e.g., statistical

metrics defining both intra-batch and inter-batch variability);

a description of how to address deviations from expected conditions and handling of

nonconforming data (data gathered during PPQ batches manufacture should not be excluded

without a documented and science-based justification).

28

All facilities, utilities and equipment have to be qualified and it has to be assured that qualification is

valid at the time of PPQ studies. The personnel involved should be properly trained and the suppliers of

critical starting and packaging materials (i.e., API and container closure system components) should be

qualified prior to these studies.

The PPQ protocol should be reviewed and approved by all appropriate departments, including the

quality unit, prior to execution. The commercial manufacturing process and routine procedures must be

followed during PPQ protocol execution and the PPQ batches should be manufactured under normal

production conditions by qualified personnel.

A PPQ report, documenting and assessing adherence to the PPQ protocol, should be prepared in a

timely manner after the manufacture of the PPQ batches. This report should:

Discuss and cross-reference all aspects of the protocol;

Summarize and evaluate all data gathered during the PPQ batches manufacture, as specified

by the protocol;

Evaluate any unexpected observations and additional data not specified in the PPQ protocol;

Summarize and discuss all manufacturing nonconformities such as deviations and OOT or OOS

test results;

Clearly describe any corrective actions or changes that should be made to the current

procedures and controls;

State a clear conclusion about the PPQ study (i.e., conclude if the data indicates that the

process met the conditions established in the protocol and if the process is considered to be in

a state of control). If not, the PPQ report should state what should be accomplished before such

a conclusion can be reached. Additional batches may be required.

The PPQ report should be reviewed and approved by all appropriate departments and quality unit prior

to submission to the competent authorities.

3.2.2.2. Concurrent validation

Usually, the PPQ study is completed prior to the commercial distribution of the drug product. However,

in exceptional circumstances, the PPQ protocol can be designed to release a batch for distribution

before complete execution of the PPQ study, which is known as concurrent validation. Concurrent

validation is applicable, with proper justification, for:

drug products rarely manufactured, for instance, due to limited demand (orphan drugs);

drug products with a short shelf-life;

drug products in short supply (drug shortage).

Any batch released concurrently should be closely accompanied throughout its lifecycle in order to

promptly evaluate eventual complaints or defects. In any of these cases, the root cause should be

identified and an evaluation should be performed to understand if the process needs to be modified.

29

3.3. Continued Process Verification

The intention of the third validation stage is to guarantee that the process remains in a state of control

during routine commercial production. All information about the process performance previously

gathered is essential to detect any unplanned deviations from the process and OOT or OOS product

results. This is crucial to identify eventual problems and determine corrective or preventive actions to

maintain the process in a state of control. [3] [20] [21]

Proper process design and process performance qualification is usually capable of anticipating

significant sources of variability and establishing appropriate detection, control and/or mitigation

strategies, as well as appropriate alert and action limits. However, new sources of variation can be

identified throughout routine commercial production, which should be properly investigated to determine

the root cause. Evaluation of intra- and inter-batch variability should be part of a continued process

verification program. [3] [20] [21]

Continued process verification can be accomplished through the following activities: [3] [20] [21]

establishment of an ongoing program to collect and evaluate data regarding the product and its

related process (process trends, quality of incoming materials and in-process and finished

product results);

development of a data collection plan and statistical methods to measure and evaluate process

stability and process capability;

ongoing monitoring and sampling of process parameters and quality attributes;

acquiring feedback on process performance from production and quality unit departments;

assessment of type of rejects, complaints, OOT or OOS results, process deviations, process

yield variations, executed batch records, process parameters and adverse event reports.

Data gathered during this stage allows to confirm that the quality attributes are being appropriately

controlled throughout the process, helps to identify undesired process variability and might suggest ways

to improve and/or optimize the process. It can be achieved by modifying some aspect of the process or

product, such as the operating conditions (ranges and set-points), process controls and component or

in-process material attributes. The planned change has to be properly described and justified.

Depending on the impact of the proposed change on product quality, additional process design and

process qualification activities might be required. [3] [20] [21]

Maintenance of the facility, utilities and equipment is also fundamental to ensure that a process remains

in control. Qualification status must be maintained through routine monitoring, maintenance and

calibration procedures and schedules and all qualification data should be assessed periodically to

determine if re-qualification is needed. Maintenance and calibration frequency should be adjusted based

on feedback from these activities. [3] [20] [21]

30

4. RELATIONSHIP BETWEEN PROCESS VALIDATION, QUALITY RISK MANAGEMENT AND

PHARMACEUTICAL QUALITY SYSTEM

The importance of quality systems has been recognized in the pharmaceutical industry and it is

becoming evident that quality risk management is a useful component of an effective pharmaceutical

quality system, which can and should be implemented throughout the different stages of a product

lifecycle. The use of science and risk based approaches at each lifecycle stage promotes innovation

and continual improvement and strengthen the relationship between pharmaceutical development,

technology transfer and manufacturing activities. [3] [26] [27] [28] [23] [25]

The product lifecycle includes several technical activities for new and existing products, as presented in

the following table: [3] [26] [27] [28] [23] [25]

Table 3 – Stages of a product lifecycle, goals and associated technical activities

Product lifecycle stage and goals Technical activities

1. Pharmaceutical Development

Goals: Design a product and its manufacturing

process to consistently deliver the intended

performance and meet the needs of patients and

healthcare professionals and regulatory authorities’

requirements.

Drug substance development

Formulation development (including container closure

system)

Manufacture of investigational products

Delivery system development (if applicable)

Manufacturing process development

Analytical method development

2. Technology Transfer

Goals: Transfer product and process knowledge

between development and manufacturing and within

or between manufacturing sites to achieve product

realization.

New product transfers during Development through

Manufacturing

Transfers within or between manufacturing and testing

sites for marketed products

3. Commercial Manufacturing

Goals: Achieving product realization, establishing

and maintaining a state of control and facilitating

continual improvement.

Acquisition and control of materials

Provision of facilities, utilities and equipment

Production (including inspection, packaging and

labelling)

Quality control and assurance

Release

Storage

Distribution

4. Product Discontinuation

Goals: Manage activities related to the terminal

stage of the product lifecycle in accordance with

regulatory requirements.

Retention of documentation

Sample retention

Continued product assessment (e.g., complaint handling

and stability testing) and reporting

31

A pharmaceutical quality system should combine diverse elements that if appropriately applied to each

product lifecycle stage allow identifying areas for continual improvement: [3] [26] [27]

Process performance and product quality monitoring – An effective system for the monitoring of

process performance and product quality provides assurance of the continued capability of

processes and controls to produce a product of desired quality and to identify areas for continual

improvement.

Corrective and preventive actions (CAPA) – Existence of a system for implementing corrective

actions and preventive actions (resulting from the investigation of complaints, product

rejections, non-conformities, recalls, deviations, audits, regulatory inspections and findings and

trends from process performance and product quality monitoring) should result in product and

process improvements and enhanced product and process understanding. A structured

approach to the investigation process should be used with the objective of determining the root

cause and, consequently, establishing actions to eliminate the cause of a detected or potential

non-conformity or other undesirable situation.

Change management – A change management system is a systematic approach to proposing,

evaluating, approving, implementing and reviewing changes (resulting from innovation,

continual improvement, outputs of process performance and product quality monitoring and

CAPA), in order to ensure that the changes are undertaken in a timely and effective manner.

Management review – A management review system provides assurance that process

performance and product quality are managed over the product lifecycle and that the

pharmaceutical quality system is reviewed regularly.

A pharmaceutical company can face various types of risk, such as: patient risk (i.e., safety and efficacy

of drug products), operational risk (i.e., operation safety and process variability), product-quality risk

(i.e., product contaminations), financial risk (i.e., product loss, reputation and legal costs) and regulatory

risk (i.e., Warning Letters, product recalls and legal actions). [26] [27]

According to ICH Guideline Q9, “risk is defined as the combination of the probability of occurrence of

harm and the severity of that harm”. Quality risk management allows to assess the probability

(occurrence), severity and detectability of the risk. Therefore, quality risk management is essential to an

effective pharmaceutical quality system, since it can provide a scientific and practical approach to

identifying, scientifically evaluating and controlling potential risks to quality. It facilitates continual

maintenance or improvement of process performance and product quality throughout the product

lifecycle. [26] [27]

An effective quality risk management approach allows assuring that a drug product with the highest

quality is delivered to the patient by providing a proactive way to identify and control potential quality

concerns during development and manufacturing. Additionally, use of quality risk management can

improve the decision-making if a quality problem arises (for instance, when a deviation is detected). It

can also facilitate better and more informed decisions and helps to prove to the competent authorities

32

that the company is able to deal properly with potential risks, which is benefic in terms of regulatory

oversight. [3] [26] [27]

Quality risk management is a systematic process for the assessment, control, communication and

review of risks to the quality of the drug product throughout the product lifecycle (refer to figure 12) and

it has two main principles: [3] [26] [27]

The risk should be evaluated based on scientific knowledge and related to the safety of the

patient;

The level of detail and documentation of the quality risk management process should be

commensurate with the level of risk.

Figure 12 – Overview of a general quality risk management process [26]

Quality risk management should include systematic processes intended to facilitate and improve

science-based decision-making regarding the risk. The following steps can be used for the design of a

quality risk management process: [3] [26] [27]

Definition of the problem and/or risk question (including relevant assumptions to identify the

potential for risk);

Gathering of background information and/or data on the potential hazard, harm or human health

impact relevant to the risk assessment;

Identification of the resources required;

Establishment of an appropriate timeline and level of decision-making for the risk management

process.

33

4.1. Risk Assessment

Risk assessment is the first part of a risk management process and consists of risk identification,

analysis and evaluation. It begins with a well-defined risk question or problem description, which should

be addressed by answering to the following fundamental questions: [3] [26] [27] [28]

1. What can fail?

2. What is the probability that the failure will occur?

3. What are the consequences (severity)?

Risk identification is a systematic use of information to identify hazards related to the risk question or

problem description, in order to answer to the first question and to identify the possible consequences.

It is a brainstorming activity and all relevant information should be taken into consideration to identify

potential failure causes to make the list as exhaustive as possible and to avoid omitting potential critical

hazards.

Risk analysis is the qualitative or quantitative process of linking the probability of occurrence, severity

of the harm and the ability to detect it (detectability) for the estimation of the risk associated with the

identified hazards.

Risk evaluation is the final step in the risk assessment. Its aim is to compare the identified and analyzed

risk against given risk criteria, considering the strength of evidence for the three fundamental questions.

In an effective risk assessment, the robustness of the data used is important because it determines the

quality of the output, which can be:

quantitative (a numerical probability is used to estimate the risk);

qualitative (risk is expressed using qualitative descriptors, such as “low”, “medium” or “high”).

4.2. Risk Control

Risk control includes decision-making to reduce the risk to an acceptable level or to accept the risk,

according to its significance. [3] [26] [27] [28]

The following questions might be useful for risk control:

Is the risk above an acceptable level?

What can be done to mitigate the risk?

What is the appropriate balance among benefits, risks and resources?

Are new risks introduced as a result of the identified risks being controlled?

34

The aim of risk reduction is to mitigate or avoid quality risk when it exceeds a specified acceptable level.

Risk reduction might include actions taken to mitigate the severity and probability of harm and/or to

improve the detectability of hazards and quality risks. Nevertheless, the implementation of risk reduction

measures can introduce new risks or increase the significance of other existing risks and, therefore, it

might be appropriate to revisit the risk assessment to identify and evaluate any possible change in risk

after implementing a risk reduction process.

Risk acceptance is a decision to accept risk, which can be a formal decision to accept the residual risk

or a passive decision when residual risks are not specified. In certain cases, even the best quality risk

management strategy might not entirely eliminate risk and, in these circumstances, it might be agreed

that quality risk is reduced to an acceptable level (which should be decided on a case-by-case basis).

4.3. Risk Communication

Risk communication consists on sharing of information about risk management and can occur at any

stage of the process. The output of the quality risk management process should be appropriately

documented and communicated, both within the company (among the involved departments) and

outside the company (among regulatory authorities and patients). The shared information might be

related to the existence, probability, severity, acceptability, control, detectability or other aspects of risks

to quality. [3] [26] [27] [28]

4.4. Risk Review

Risk review should be continuously performed throughout the quality management process. The output

of the risk management process should be reviewed to take into account new knowledge and experience

and might include reconsideration of risk acceptance decisions. An appropriate review frequency should

be implemented based on the level of risk. [3] [26] [27] [28]

4.5. Quality Risk Management Tools in the Pharmaceutical Industry

Using appropriate tools is essential for an effective quality risk management process. Several tools can

be applied to several aspects of pharmaceutical quality and different stages of the product lifecycle (for

example, development, validation and manufacturing). [3] [26] [27] [28] [25]

4.5.1. Basic risk management techniques

Some techniques are extremely simple and can be used to structure risk management by organizing

data and facilitating decision-making, such as:

35

Flowcharts;

Check Sheets (forms);

Process Mapping – refer to Appendix 2;

Cause and Effect Diagrams (also known as Ishikawa or fishbone diagrams) – refer to figure 13.

Figure 13 – Template of a Cause and Effect Diagram. Adapted from [25]

Some statistical tools can also be used to support and facilitate quality risk management in the

pharmaceutical industry, such as, control charts, histograms and Pareto charts. Other tools can be used

in the risk management process, such as, Preliminary Hazard Analysis (PHA), Failure Mode Effects

Analysis (FMEA), Failure Mode Effects and Criticality Analysis (FMECA), Fault Tree Analysis (FTA),

Hazard Analysis and Critical Control Points (HACCP) and Hazard Operability Analysis (HAZOP). [3] [26]

[27] [28] [25]

4.5.2. Preliminary Hazard Analysis (PHA)

PHA is a tool of analysis based on applying prior experience or knowledge of a hazard or failure to

identify future hazards and events that might cause harm, as well as to estimate their probability of

occurrence. This is a simple tool that is most commonly used early in the development of a project when

there is little information on design details or operating procedures and a more extensive technique is

not applicable. Usually, hazards identified in the PHA are further assessed with other risk management

tools described below. This tool can be applied to facilities, products, processes or systems and consists

of:

1. identification of the possibilities that the risk event happens,

2. qualitative evaluation of the extent of possible injury or damage to health that could result;

3. relative ranking of the hazard using a combination of severity and probability of occurrence;

4. identification of possible CAPA.

Equipment Process People

Materials Environment Measurements

36

4.5.3. Failure Mode Effects Analysis (FMEA)

FMEA is used to identify potential failure modes for processes and their expected effect on outcomes

and/or product performance, based on product and process understanding. This tool provides a

prospective analysis designed to answer the question: “What would happen if this failure occurs?”. Once

failure modes are established, risk reduction can be used to eliminate, reduce or control the potential

failures. FMEA methodically breaks down the analysis of complex processes into manageable steps. It

is a useful tool for summarizing the important modes of failure, factors causing these failures and the

likely effects of these failures.

4.5.4. Failure Mode Effects and Criticality Analysis (FMECA)

FMECA is an extension of the FMEA tool to incorporate an evaluation of the degree of severity (S) of

the consequences, their respective probabilities of occurrence (O) and their detectability (D). These

parameters are rated and, afterwards, the risk priority number (RPN) is calculated by multiplying S, O

and D values. RPN is used to access the risk of unit operations, which form the whole process. After

determining all the RPNs, the failure mode with highest RPN should be given highest priority for

establishing preventive actions that might be appropriate to minimize risks.

4.5.5. Fault Tree Analysis (FTA)

The FTA tool is an approach that assumes failure of the functionality of a product or process. This tool

provides a retrospective analysis designed to answer the question: “What caused this failure to

happen?”. It evaluates system failures one at a time but can combine multiple causes of failure by

identifying causal chains. The information is organized in the form of a fault tree diagram. At each level

in the tree, combinations of fault modes are described with logical operators (e.g., and, or). This tool is

useful to establish the pathway to the root cause of the failure.

4.5.6. Hazard Analysis and Critical Control Points (HACCP)

HACCP is a systematic, proactive and preventive tool for assuring product quality, reliability and safety.

This tool applies technical and scientific principles to analyze, evaluate, prevent and control the risk or

adverse consequences of hazards due to the design, development, production and use of products.

HACCP can be used to identify and manage risks associated with physical, chemical and biological

hazards and it is most useful when product and process understanding is sufficiently comprehensive to

support identification of critical control points. This tool consists of the following seven steps:

1. perform a hazard analysis and identify preventive measures for each step of the process;

2. determine the critical control points;

3. establish critical limits;

4. establish a system to monitor the critical control points;

5. establish the corrective actions to be taken when monitoring indicates that the critical control

points are not in a state of control;

6. establish system to verify that the HACCP system is working effectively;

37

7. establish a record-keeping system.

4.5.7. Hazard Operability Analysis (HAZOP)

HAZOP is a tool based on the assumption that risk events are caused by deviations from the design or

normal operating conditions. It is a systematic brainstorming technique for identifying hazards using

“guide-words” (e.g., No, More, Other Than, Part of, etc.), which are applied to relevant process

parameters to help identify potential deviations from normal use or design intentions.

As is the case with HACCP, the output of a HAZOP analysis is a list of critical operations/parameters

for risk management, which facilitates regular monitoring of critical points in the manufacturing process.

4.6. Quality Risk Management as part of Process Validation

Quality risk management tools are extremely useful when applied as part of process validation

(particularly during PPQ), due to the high amount of validation activities required. Process validation is

essential to ensure the production of a safe product that minimizes the risk to patients and the tools

mentioned above can be applied in process validation to minimize process risk. Risk management tools

help to define the process and identify crucial areas and/or steps in that process, areas of risk and/or

hazard and critical control points. The questions mentioned in chapter 4.1 should be asked when

applying risk assessment to process validation. The results from the risk assessment often dictate the

effort needed to reduce specific risks to acceptable levels and it helps to distinguish between critical and

non-critical process steps and parameters, which facilitates the design of a process validation study. [3]

[26] [27] [28] [25]

Risk management tools can be used alone or in combination to evaluate the scope of process validation

activities. The following are also benefits of using risk-based approaches in process validation: [3] [26]

[27] [28]

Improves process understanding;

Facilitates process troubleshooting;

Helps to meet regulatory requirements;

Identifies critical parameters that can affect product quality;

Determines whether a process is robust or not.

38

5. TECHNOLOGY TRANSFER

Technology transfer involves transfer of product and process knowledge to achieve product realization.

It includes all the activities required for successful progress from pharmaceutical development (R&D) to

production (for new products) or from one manufacturing site to another (for marketed products). [3] [23]

[29] [30] [31] [25]

Several technical aspects need to be taken into consideration to allow proper evaluation and validation

of the manufacturing process prior to start routine production of the product for commercial purposes.

There are inputs, outputs and controls associated with each unit operation of a manufacturing process.

A proper correlation between process inputs (material attributes and process parameters), their

associated manufacturing controls and process outputs (quality attributes) is crucial for successful

technology transfer. Inappropriate understanding regarding the relationship between process inputs and

outputs and lack of efficient controls can result in a process not properly controlled. This may lead to

extensive product losses, batch rejection, difficulties with regulatory submissions and, ultimately,

preclude submission approval. [3] [23] [29] [30] [31] [25]

Identification of all unit operations and their associated equipment is crucial when selecting those

parameters and attributes that are considered critical and, therefore, need to be controlled. All relevant

information about the product and the process obtained during the development phase should also be

properly reviewed and evaluated. [3] [23] [29] [30] [31] [25]

According to ICH Guideline Q8(R2), “A CPP is a process parameter whose variability has an impact on

a CQA and therefore should be monitored or controlled to ensure the process produces the desired

quality”. Therefore, it is crucial to identify and to determine the functional relationships that link CPPs

and CMAs to product CQAs, in order to establish a proper control strategy, which can be simplified and

improved by using a risk-based approach. The product quality attributes classified as CQAs usually

include product appearance, assay and impurities, which are critical because they have the potential to

be impacted by the formulation and/or manufacturing process variables. Bacterial endotoxins, product

sterility and particulate matter are also considered to be CQAs for injectable pharmaceutical products.

CQAs are generally ensured through a good pharmaceutical quality system and by implementing an

effective control strategy. [3] [23] [29] [30] [31] [25]

A control strategy may include control of input materials, process monitoring and controls, design space

around unit operations, in-process controls and final product specifications to ensure consistent quality.

The design space can be defined as the multidimensional combination and interaction of input variables

that have been demonstrated to provide assurance of quality (i.e., operating within the design space

leads to consistent product quality). PAT can be applied as part of a control strategy, by continuously

monitoring of critical process inputs, in order to maintain the process within an established design space.

39

The main steps for the selection of CPPs and establishment of a control strategy are as follows: [3] [23]

[29] [30] [31] [25]

Identify CQAs for the drug product;

Select API, excipients, container closure system components and other product contact materials;

Define all unit operations and process flowchart;

Define all product and process specification limits;

Characterize and validate all analytical methods;

Complete quality risk management for all critical unit operations and materials;

Explore the design space for all key factors identified during the risk assessment;

Identify and evaluate CPPs and CMAs that can have an effect on product CQAs.

Appendices 2 to 4 show an example of a schematic approach applied to facilitate and improve

technology transfer of a certain liquid injectable product (process mapping, process flowchart and

FMECA). Additionally, a risk assessment regarding the transfer of the same product from one

manufacturing site to another is presented in Appendix 5. The process map lists process parameters,

material attributes and quality attributes for each unit operation of a certain manufacturing process. The

process map provides a basis for the interdependencies between inputs, processing steps and desired

outputs and, therefore, this information can be used to define equipment/facility specific CPPs, CMAs

and CQAs. The process flowchart is a schematic view of the manufacturing process, which can also

simplify the identification of critical inputs and outputs. Risk management tools (e.g., FMEA and FMECA)

are extremely helpful to identify potential failure modes for the manufacturing process and their expected

effect on the outputs.

5.1. Review of the drug product information

5.1.1. Drug product formulation [3] [23]

All raw materials listed in the drug product formulation (i.e., drug substance(s) and excipients) should

be compatible with each other.

The properties of the drug substance that can influence the manufacturability and performance of the

drug product (for instance, water content and particle size) should be properly evaluated. An overage of

a drug substance can be used to compensate for losses during manufacture. Although the use of an

overage is not recommended, it is acceptable if properly justified considering the safety and efficacy of

the drug product.

Additionally, the excipients chosen, their concentration and the characteristics that can influence the

drug product manufacturability or performance should be assessed and it should be proven that the

excipients provide their intended functionality throughout the drug product shelf-life.

40

5.1.2. Drug product specifications and characteristics [3] [23]

The physicochemical and microbiological attributes of the drug product should be verified. In the case

of injectable pharmaceutical products, particulate matter, sterility and bacterial endotoxins should

always be part of the finished product specifications. Different attributes can be identified for liquid or

solid (lyophilized) injectable products, as presented in tables 5 and 6.

Table 4 – Example of drug product release specifications for a liquid injectable product

Test Parameters Acceptance Criteria

Appearance Clear, yellow solution free from visible signs of contamination

Identification Retention time of the major peak in the sample chromatogram corresponds to that of the peak in the reference or house standard chromatogram

pH 3.5 to 4.5

Volume in Container ≥ 5.0 mL

Assay 95.0 % to 105.0 % of the labeled amount

Impurities – Impurity X ≤ 1.0 %

Impurities – Impurity Y ≤ 0.5 %

Impurities – Impurity Z ≤ 0.5 %

Impurities – Any other individual impurity ≤ 0.2 %

Impurities – Total impurities ≤ 2.2 %

Residual Solvents This product complies with the requirements, option 1, in the USP general chapter <467> Residual Solvents

Particulate matter – Sub-visible particles ≥ 10 µm ≤ 6000 particles/vial

Particulate matter – Sub-visible particles ≥ 25 µm ≤ 600 particles/vial

Bacterial Endotoxins ≤ 1.0 endotoxin units per mg of drug substance

Sterility Sterile

Table 5 – Example of drug product release specifications for a lyophilized injectable product

Test Parameters Acceptance Criteria

Appearance White cake or powder essentially free from visible contaminants

Identification (Method A) The retention time of the drug substance should be within 5% in the sample and reference standard chromatograms

Identification (Method B) The sample exhibits a spectrum comparable to that of the reference standard

Completeness of solution The entire cake yields a clear solution, when dissolved and diluted with sterile WFI

pH (solution reconstituted with sterile WFI) 5.0 to 7.0

Water content ≤ 0.5 % per vial

Assay 95.0 % to 110.0 % of labeled amount

Impurities – Unknown Impurity ≤ 0.3 %

Impurities – Total Known and Unknown Impurities ≤ 0.6 %

Uniformity of Dosage Units (Weight variation) Meets the requirements

Residual solvents This product complies with the requirements, option 1, in the USP general chapter <467> Residual Solvents

Particulate matter – Sub-visible particles ≥ 10 µm (reconstituted with sterile WFI)

≤ 6000 particles/vial

Particulate matter – Sub-visible particles ≥ 25 µm (reconstituted with sterile WFI)

≤ 600 particles/vial

Bacterial Endotoxins ≤ 2.5 endotoxin units per mg of drug substance

Sterility Sterile

41

The product sensitivity should be evaluated in order to establish adequate measures to protect the

product throughout the manufacturing process and allow obtaining a finished product within

specifications.

5.1.2.1. Product sensitive to light

A product sensitive to light must be appropriately protected from light, as follows:

using amber containers;

using yellow lights instead of white lights in all the rooms where the product is manipulated;

avoid using the light of the preparation tank, if applicable, during the batch preparation;

protecting the samples taken for testing by wrapping the containers with aluminum foil;

maintaining the finished product containers inside the respective boxes.

5.1.2.2. Product sensitive to oxygen

The manufacture of products sensitive to oxygen should be performed using an inert atmosphere. The

headspace of the tank during the batch preparation and the headspace of the containers during the

filling process should be replaced by an inert gas. Although the gas more commonly used is Nitrogen,

other gases can be used, such as Argon and Carbon Dioxide. Additionally, whenever possible, the size

of the container should be chosen to obtain a minimum headspace after filling.

5.1.2.3. Product sensitive to heat

Different phases of the manufacturing process might require different temperatures. The holding times

during the manufacturing process and the finished product storage is normally done at cold conditions.

A maximum total time at room temperature should be established for these products – refer to chapter

5.5.

5.1.3. Container closure system

The rationale for selection of the container closure system for the commercial product should take into

consideration the intended use of the drug product and the suitability of the container closure system

for storage and transportation (shipping). The choice of primary packaging materials should consider

protection of the drug product (from moisture and light, for instance), compatibility of the materials of

construction with the product and safety of the materials of construction.

5.1.3.1. Container closure integrity testing [32] [33]

The integrity of the container closure system should be properly evaluated to demonstrate that it

provides the product adequate protection and prevents microbiological contamination, in order to ensure

the maintenance of product physicochemical characteristics and sterility over its shelf-life.

42

Package integrity testing continues throughout the lifecycle of the product and should occur during the

following phases: initial development of the product packaging system, routine production and shelf-life

stability assessments. New product packaging integrity testing should be done when there are major

changes in the package design and materials or whenever there are changes in the manufacturing

processing conditions (such as sterilization conditions). The container closure system should be always

validated after exposure to worst-case sterilization processing (typically maximum time and

temperature) to demonstrate microbial barrier integrity.

Integrity tests can be divided in physical and microbiological methods. Microbiological tests are usually

accomplished by immersion of the container closure system into a liquid previously inoculated with the

challenge microorganism (the microorganism challenge inoculation level should be multiple orders of

magnitude greater than the natural challenge level expected during shelf-life of the product). Physical

tests may include dye immersion tests, chemical penetration tests, pressure and vacuum decay tests,

high-voltage leak detection, visual examination for glass cracks and gas leakage or package headspace

analysis. Physical testing has several advantages over microbiological testing, which may include

greater sensitivity, ease of use, rapid speed of testing and lower cost.

Generally, during initial packaging development both physical and microbiological studies are conducted

to assess integrity. Afterwards, physical tests may be used to confirm the integrity of the container

closure system provided that the sensitivity of these methods has been favorably correlated to sensitivity

of microbiological methods (i.e., if physical test methods have proven to have a sensitivity comparable

to or greater than that of microbiological methods during the packaging development stage). In this case,

microbiological testing can be considered unnecessary for shelf-life stability assessment.

During routine production, physical measurements may be conducted to determine whether the

packaging system is operating consistently within predetermined performance acceptance ranges.

Regarding fusion type containers (e.g., ampoules), container closure integrity should be one hundred

percent verified during routine production.

5.1.3.2. Assessment of Extractables and Leachables [34] [35] [36] [37]

The possible interaction between pharmaceutical products and its contact surfaces (primary packaging

components, equipment and materials used during the product manufacture) is a huge concern,

particularly for injectable drug products, which are directly administered in the blood system.

All materials used for the manufacturing process should be proven to be compatible with the product.

Nevertheless, the contact duration of the product with these materials is limited to production. On the

other hand, the product is in contact with its container closure system components throughout the shelf-

life and, therefore, a possible interaction between them is even more critical. These individual

interactions should be investigated for each drug product (typically during stability studies).

43

Extractables are substances that can be extracted from a material when in the presence of an extraction

solvent under laboratory conditions (which usually accelerate or exaggerate the normal manufacturing,

storage or use conditions). Extractables have the potential to leach into a drug product under normal

storage or use conditions and, therefore, become leachables (i.e., extractables are potential

leachables).

Leachables are substances that are present in the drug product due to its contact with the container

closure system or other product contact material. The major concerns regarding leachables are due to

their potential safety risk to patients and potential compatibility risk for the drug product. Leachables

should be properly identified and quantified in order to assess the level of patient exposure and,

consequently, the safety risk caused by an individual leachable and to predict any compatibility issues

with the drug product. It is recommended that any leachables assessment be preceded by an

extractables assessment in order to facilitate the establishment of extractables-leachables correlations.

Extractables assessments can be used for several purposes, such as, selection of appropriate materials

for the manufacture of each drug product, characterization and qualification of container closure system

components, establishment of qualitative and quantitative extractables-leachables correlations and

establishment of the worst-case potential leachables profile.

An extractables assessment requires performance of an extraction study in order to generate

extractables profiles. An extraction study has two major steps: generation of the extract (extraction) by

treating a material with a solvent to remove soluble substances and testing the extract (characterization).

Extraction is a process influenced by several factors, such as, time, temperature, surface area to volume

ratio and extracting medium. Extraction processes are usually performed under worst-case process or

storage conditions to allow completion in a reasonable time frame but should not be so aggressive that

they change the nature of the resulting extractables profile. After generation of the extract, a thorough

chemical characterization should be performed and the level of each extracted chemical entity should

be specified.

The purpose of leachables assessments is to investigate both qualitative and quantitatively the

leachables profile obtained for a certain drug product in order to understand the impact of leachables

on patient safety and drug product quality and stability.

A leachables study is performed on the actual drug product, with the actual packaging in which it will be

commercialized and manufactured under conditions that reflect the commercial production process. It

is intended to discover, identify and quantify impurities derived from the container closure system

components or other product contact materials that have migrated and accumulated in the drug product

under its actual manufacturing, storage and use conditions. Leachables studies can be performed under

accelerated storage conditions but they cannot be limited to these conditions and should include real-

time assessment.

44

5.1.3.3. Glass delamination [3] [38] [39] [40] [41]

Glass delamination is generally described as the detachment of thin layers from the inner surface of

glass containers, leading to the appearance of glass fragments (lamellae) in a drug product solution.

Although glass has many advantages over other packaging materials, glass delamination is a well-

known disadvantage. When glass delamination occurs, the glass fragments are released from the inner

surface of the glass container directly into the drug product, affecting its quality. This phenomenon is

particularly relevant for water-based liquid injectable products. Some conditions have the potential to

negatively influence the chemical durability of the inner surface of glass containers and, therefore, can

be considered as risk factors for glass delamination.

Manufacturing process of the glass containers:

Regarding the manufacturing process, two different types of glass containers are used for injectable

drug products: molded and tubular. Molded containers are formed in a single high heat cycle, where the

glass is melted, poured and then blown or pressed into a mold. Generally, the glass in molded containers

has a composition which is relatively low in silicon and high in alkali / alkaline elements, lowering the

working temperature and resulting in interior container surfaces with chemical homogeneity. On the

other hand, tubular containers are made from glass tubes and require two high heat cycles. The tubing

is made first and, then, it is segmented / converted in a second heating process into the final container

design (vials, ampoules or syringes). The converting process should be carefully controlled in order to

assure that the interior container surfaces maintain the resistance to chemical attack. Inadequately

converting processes can lead to evaporation of some glass components, changing the chemistry and

lowering the glass resistance. Tubular containers usually have higher amounts of silicon and lower

amounts of alkali / alkaline elements than molded containers. Although both molded and tubular glass

containers for injectable products have high chemical durability, tubular containers are generally less

resistant than molded containers and, therefore, more likely to release glass fragments into the products

that they contain. Nevertheless, proper control of the converting process results in tubular containers

with the equivalent non-delamination of molded containers.

Type of glass and glass composition:

Glass for pharmaceutical packaging can be classified as type I (borosilicate glass) (refer to table 6),

type II (treated soda-lime-silica glass) or type III (soda-lime-silica glass) based on its hydrolytic

resistance. Glass with a lower hydrolytic resistance is more prone to glass delamination and, therefore,

the type of glass usually used for injectable drug products is type I glass, which has high chemical

durability and low reactivity. For drug products formulated at low pH (pH < 7) or aqueous neutral

solutions, any kind of type I glass containers can be used. On the other hand, for drug products

formulated at high pH and/or with buffers (organic acids such as citrate, tartrate and glutarate), only

untreated borosilicate glass should be used. Ammonium sulfate treatment is used to remove the alkali

components from the container surface, which can be required to enhance drug stability since it reduces

the propensity to pH shift. However, this type of treatment is very aggressive, which can lead more easily

45

to the occurrence of delamination and, therefore, the use of sulfur treated containers should be restricted

to products with pH ≤ 7.

Glass in its pure form consists of silicon dioxide with a melting point of approximately 1700 ºC. However,

this is rarely used commercially because of the cost of working at these elevated temperatures. Added

network modifiers, such as sodium, potassium, or boron oxide, lower the melting point and lower the

chemical durability, whereas added network stabilizers, such as calcium and aluminum oxides, improve

the durability of the glass. Colored glass (e.g., amber glass) is produced by transition metal oxides such

as iron oxides. All additives to pure silicon dioxide, as well as silicon itself, can be viewed as potential

extractables from glass containers.

Table 6 – Typical borosilicate glass composition. Adapted from [41]

Main elements Molded containers (%) Tubular containers (%)

SiO2 70.5 74

Al2O3 5.5 6

Na2O 7.5 7

K2O 1.5 1

CaO 1 1

BaO 2.5 0-1

B2O3 11.5 11

Drug product formulation:

Basic solutions (formulated at high pH) and/or solutions with buffers, chelating agents and organic acids

are more aggressive to the glass and, therefore, more susceptible to this phenomenon.

Sterilization process:

Drug products sterilized by terminal sterilization are more likely to be affected by glass delamination

since this process can have a significant effect on the glass stability.

Storage time:

The time duration that the drug product is exposed to the inner surface of the container is directly related

to the potential for glass lamellae formation, which is the reason for this phenomenon to be usually only

detected during the product shelf-life. Chemical interactions might occur during the shelf-life of the

product which can lead to the presence of low concentrations of glass elements in the product.

Storage temperature:

Drug products stored at room temperature have a higher risk of glass delamination occurrence than

drug products stored at refrigerated or frozen conditions.

46

Glass delamination is the result of a complex chemical reaction between the drug product and the inner

surface of the glass container and the risk factors mentioned above influence the degree of this reaction.

This phenomenon can be minimized by proper selection of the type of glass (and glass composition),

appropriate selection and qualification of suppliers and proper quality control of the incoming vials.

The inner surface durability of glass containers should always be evaluated. Aggressive test solutions

(usually, basic solutions and/or solutions with buffers) can be used to predict the propensity of the

internal glass surface to delaminate. Nevertheless, for a proper risk evaluation, individual screening (i.e.,

glass delamination studies with the drug product itself) should be conducted when relevant, particularly

when one or more of the above conditions exist. However, these risk factors alone (or the lack of risk

factors) are not predictive of glass delamination, which is why individual testing is important. It can be

done by placing the drug product and the candidate container(s) together under accelerated conditions,

which allows to identify potential problems that might occur throughout the shelf-life of the product in a

few time (particularly since delamination is usually only detected after months or even years of product

storage). This evaluation should be done prior to the drug product commercialization in order to allow

the selection of the right container and to avoid future product recalls due to glass delamination.

The mechanisms that lead to glass attack by water-based liquid products are mainly related with ion

exchange and dissolution, depending on the pH value. The primary attack mechanism at acidic pH is

the exchange of hydrogen ions from the aqueous phase with the alkali ions from the glass, but the silica

network of the glass is not affected (refer to equation 1). On the other hand, the primary attack

mechanism at basic pH is the dissolution of the silica network of the glass by hydroxide ions (refer to

equations 2 and 3). A third mechanism may occur, which involves dissolution and reaction (particularly

in solutions with buffers). In this case, not only are the elements of the glass dissolving into the product

but some elements from the drug product interact with the glass, which might create a layer that can

detach easily from the glass surface.

𝑆𝑖𝑂𝑁𝑎 (𝑔𝑙𝑎𝑠𝑠) + 𝐻+ → 𝑆𝑖𝑂𝐻 + 𝑁𝑎+ Equation 1

𝑆𝑖𝑂2 (𝑔𝑙𝑎𝑠𝑠) + 2𝐻2𝑂 ↔ 𝐻4𝑆𝑖𝑂4 Equation 2

𝐻4𝑆𝑖𝑂4 + 𝑂𝐻− ↔ 𝐻3𝑆𝑖𝑂4− + 𝐻2𝑂 Equation 3

If glass delamination is predicted in an early phase, some approaches can be used to mitigate the risk,

as follows:

using a different type I glass composition to solve the problem of drug product / glass chemistry

incompatibility;

trying glass containers from different manufacturers due to differences in glass composition and

manufacturing processes;

using quartz-coated containers, since pure SiO2 of quartz is almost inert;

47

consider using plastic containers, which have their own issues but might solve a problem for a

specific drug product that is not compatible with any glass container;

as a last resort, consider modifying the formulation of the drug product.

5.1.4. Proposed manufacturing process [3] [23]

The critical formulation attributes should be considered together with the available manufacturing

process options in order to address the selection of the manufacturing process and confirm the

appropriateness of the components. Appropriateness of the equipment, filters and tubes to be used

should also be evaluated. Process development studies should provide the basis for process

improvement, process validation and any process control requirements. If possible, the critical process

parameters that must be monitored or controlled to ensure that the product is of the desired quality

should be identified. The selection, the control and any improvement of the manufacturing process

(intended for commercial production batches) should be explained.

In the case of injectable pharmaceutical products (and other products intended to be sterile), it should

be verified that an appropriate method of sterilization for the drug product and primary packaging

components was selected and the choice properly justified. The preferred sterilization method is moist

heat sterilization instead of aseptic filling. Any product that is not heat sensitive must be terminally

sterilized. Product approach sterilization parameters can be used for products that have some heat

sensitivity, providing that F0 achieved during sterilization is not lower than 8 minutes (refer to

Appendix 1).

The description of the manufacturing process development should be accompanied with the description

of measurement systems that allow monitoring of critical attributes and at least tentative control

strategies.

5.2. Validation of analytical methods and cleaning validation

5.2.1. Validation of analytical test methods [3] [24] [25]

Limit of detection, limit of quantification, precision and accuracy must be characterized for all analytical

test methods. All methods should be properly validated prior to product and process characterization

studies and the design and implementation of process controls. Any Microbiological method should be

validated to confirm that the product does not influence the recovery of microorganisms.

5.2.2. Cleaning validation [3] [24] [25]

Cleaning validation should be performed in order to confirm the effectiveness of any cleaning procedure

for all product contact equipment. Sufficient data from the verification should be available to support a

conclusion that the equipment is clean and can be released for further use. Adequate cleaning

48

procedures are essential to minimize the risk of contamination and cross-contamination (if the facility

manufactures multiple products), operator exposure and environmental effects.

Limits for the carryover of product residues should be based on a toxicological evaluation and the

justification for the selected limits should be properly documented in a risk assessment. Limits for the

removal of any cleaning agents used should also be established. Acceptance criteria should consider

the potential cumulative effect of multiple items of equipment in the process equipment train. The

influence of the time between manufacture and cleaning and the time between cleaning and use should

be considered to define dirty and clean hold times for the cleaning process.

A worst-case product approach may be used as a cleaning validation model. In this case, a scientific

rationale should be provided for the selection of the worst-case product and the impact of the

introduction of new products to the manufacturing site. The worst-case product may be determined

based on the following criteria: solubility, cleanability, toxicity and potency.

Cleaning validation protocols should specify the locations to be sampled, the rationale for the selection

of these locations and define the acceptance criteria. Sampling is usually carried out by swabbing and/or

rinsing however other methods may be used depending on the equipment. Analytical methods should

be challenged in combination with the sampling methods to demonstrate both the levels of recovery

from the equipment and the reproducibility of the results. Recovery should be shown to be possible from

all product contact materials sampled in the equipment with all the sampling methods used. The cleaning

procedure should be performed an appropriate number of times based on a risk assessment and meet

the acceptance criteria in order to prove that the cleaning method is validated.

5.3. Materials and equipment preparation

The preparation of all materials and equipment to be used for the manufacturing process of an injectable

product is critical in order to ensure the quality and quantity of the materials/components and to avoid

contaminations during production.

5.3.1. Washing and sterilization/depyrogenation of the container closure system components [3] [17]

[42]

The components of the container closure system have to be washed and sterilized with qualified

equipment according to validated procedures. These components can be prepared in the production

plant or can be received pre-sterilized by the manufacturer.

Glass containers (e.g., vials, ampoules) are usually washed and depyrogenated in the production plant

immediately prior to production. The washing is done using a washing machine and water for injection

at least for the last rinsing step. Dry heat depyrogenation consists in the thermal destruction of bacterial

49

endotoxins and is done following the washing process using a depyrogenation tunnel. A tunnel typically

includes three zones: a load / pre-heat zone to pre-warm the glassware, a hot zone where the glassware

is exposed to process temperature (usually between 250ºC and 400ºC) for sufficient time to achieve

sterilization / depyrogenation and a cool zone to bring the glassware to room temperature prior to exiting

the tunnel.

Stoppers can be provided ready-to-sterilize (RTS) or ready-to-use (RTU). RTS stoppers are packaged

in steam sterilizable bags and have to be sterilized in the production plant immediately prior to

production. On the other hand, RTU stoppers are pre-sterilized by the manufacturer and provided in

sterile double or triple bags, in order to maintain the closure integrity and sterility until filling in aseptic

conditions. The stoppers manufacturer has to demonstrate that validated washing cycles using water

for injection and, for the RTU stoppers, also validated sterilization cycles are applied. The manufacturer

have to test and provide acceptable results for particles, bioburden, bacterial endotoxins, sterility and,

in certain cases, residual moisture (a quality certificate should be provided). Moisture content is

particularly critical for lyophilization stoppers (i.e., stoppers used for lyophilized products). These

stoppers must have low moisture content (typically, residual moisture content should be equal or less

than 0.3 %), in order to prevent moisture release from the stoppers to the product throughout its shelf-

life. [43]

5.3.2. Selection and weighing of the raw materials (API and excipients) [3] [25]

Only raw materials from qualified manufacturers/suppliers should be used for the manufacture of the

drug product. All batches of each raw material should be accompanied with a certificate of analysis

(COA), which reflects the supplier’s test results for each specific batch being provided. If the raw material

has a monograph in the Pharmacopeia, the specifications should be in accordance with the

Pharmacopeia followed by the market the finished product is intended to be submitted to. For instance,

if the drug product is intended to be commercialized in the United States or in Europe, the raw materials

used for its production must comply with the specifications from the United States Pharmacopeia (USP)

or European Pharmacopoeia (EP) monograph, respectively. Usually, changing the

manufacturer/supplier of the excipients is not critical to the process provided that all comply with the

relevant Pharmacopeial monograph specifications. On the other hand, changing the manufacturer of

the API is considered critical and, in this case, the compounding process needs to be revalidated using

the new API source.

Each raw material should be stored and handled according to its sensitivity to light, heat, oxygen and

humidity. The information presented in the Pharmacopeial monograph and Material Safety Data Sheet

(MSDS) should always be consulted in order to determine the appropriate conditions and equipment to

be used during the raw material sampling and weighing and during the manufacture of the drug product.

It is crucial to prevent the raw material degradation and to ensure personnel protection. Different

approaches should be followed according to the raw material sensitivity, as follows:

50

Raw materials sensitive to light – The weighing of raw materials sensitive to light should be

performed under yellow lighting and the weighing container should be amber or wrapped with

aluminum foil, in order to avoid direct exposure of the raw material to white light.

Raw materials sensitive to heat – The weighing of raw materials stored in the fridge or in the

freezer should be performed in a short period of time after equilibration of the raw materials to

room temperature. The weighed amount should be immediately used for production or stored

at the same storage conditions as the original container (fridge or freezer), as appropriate.

Raw materials sensitive to oxygen – These raw materials should be weighed in containers with

the lower headspace possible. Immediately after weighing, the headspace of the original

container and of the weighed container should be overlaid with an inert gas (usually, Nitrogen),

in order to replace the oxygen and prevent the degradation of the raw material.

Raw materials sensitive to humidity (hygroscopic) – Excessive exposure of hygroscopic raw

materials to the environment should be avoided. These raw materials should be weighed in

containers with the lower headspace possible. In certain cases, these raw materials are weighed

in controlled humidity environments and the headspace of the original container and of the

weighed container are overlaid with an inert gas (e.g., Nitrogen), to avoid contact with water

molecules.

The weighing of the raw materials has to be performed and verified by trained personnel and the scales

calibrated on a regular basis, to ensure that the exact amounts are weighed and used in the preparation

of the bulk solution.

5.4. Compounding (preparation of the bulk solution)

For liquid parenteral solutions, compounding consists in the preparation of the bulk solution, following

the defined formulation and compounding process. The API and the excipients are dissolved in a

vehicle, which could be aqueous, normally water for injection, or an oil. The equipment used for

compounding are jacketed compounding tanks equipped with mixers and temperature sensors. For

some products sensitive to oxygen, other tank accessories are required like sparging elements for inert

gas sparging and dissolved oxygen sensors. The sequence of addition of the raw materials, the mixing

speeds and the mixing times used can influence the dissolution of each raw material and the

homogeneity of the final bulk solution. The influence of the compounding process on the product quality

should be evaluated and the process parameters used properly validated for each batch size. Ranges

of mixing times and mixing speeds should be challenged to ensure that complete dissolution and

homogenization occur. Usually, a range of mixing times and mixing speeds is established in the PPQ

protocol for each compounding step based on the developmental experience as well as the current

experience of the site with similar products, batch size and compounding tanks. This range is used as

a reference and can be adjusted, if needed, during actual production of the PPQ batches to achieve

51

proper dissolution or homogenization. At the end of the compounding process, samples from the top

and bottom of the preparation tank are collected and tested to verify bulk solution homogeneity. [3]

The selection of the tank to be used for each batch should be based on the product characteristics and

process requirements.

5.4.1. Compatibility of the material of construction with the bulk solution [3] [44]

Usually, stainless steel 316L tanks (refer to figure 14) are used for preparation of solutions in the

pharmaceutical industry, since this material is considered chemically inert, has a high corrosion

resistance and is easily cleaned and sterilized. Glass lined tanks have to be used when the bulk solution

is not compatible with stainless steel. A compatibility study should be performed to ensure that the

product is compatible with the material of construction of the tank taking into consideration the

temperatures used during the compounding process, the maximum expected compounding time and

holding time after compounding. These studies are normally performed at the R&D stage.

Figure 14 – Stainless steel tank [44]

5.4.2. Batch size [3]

The tank operating capacity should be as close as possible to the final solution volume, in order to

decrease the tank headspace. This is particularly critical for products sensitive to oxygen since a lower

tank headspace leads to a lower contact of the bulk solution with oxygen and, therefore, minimizes

degradation.

5.4.3. Compounding process controls [3]

The presence of any heating or cooling step in the compounding process requires the use of a jacketed

tank to heat or cool down the solution until the desired temperature. The need to sparge the solution

52

with an inert gas to remove the dissolved oxygen requires the use of a sparging element. The controls

associated to the compounding process should be taken into consideration (e.g., temperature and

dissolved oxygen monitoring / control) for the tank selection, which should have sensors to measure the

desired parameters during the compounding process for real-time monitoring and control.

5.5. Holding times

Maximum holding times have to be defined for each product / process according to the product

sensitivity, the product compatibility with its contact materials during the manufacturing process and in

order to avoid Bioburden growth. Different holding times may be established according to the

characteristics of the product and the process. [3]

5.5.1. Maximum compounding time [3]

This holding time is calculated from the addition of the first raw material (which is considered as the

beginning of the compounding process) until the tank is hermetically closed (which is considered as the

end of the compounding process). Usually, a safety margin (of one or two hours, for instance) is added

to the maximum compounding time calculated during the manufacture of the PPQ batches.

5.5.2. Maximum bulk holding time [3]

A maximum bulk holding time is typically evaluated for one PPQ batch, in a portion of the bulk solution

left in the compounding or transference tank after the end of the compounding/transference process.

Samples are collected at different time points and evaluated in terms of physicochemical and

microbiological attributes. The results obtained at each time point should be compared with time zero

bulk results (obtained at the end of compounding) in order to understand the behavior of the product

and to verify if there was an increase in bioburden. This holding time can be calculated as follows,

according to the type of product and to the process characteristics:

Maximum holding time between the end of compounding and the end of filling – This holding

time is generally established for liquid products and is calculated from the time the tank is

hermetically closed until the end of filling (last unit is filled).

Maximum holding time between the beginning of API addition and the beginning of the

lyophilization cycle – This holding time is applicable to lyophilized products due to the instability

of the API in the liquid form. It is calculated from the beginning of the API addition to the

preparation tank and the beginning of the lyophilization cycle (freezing phase) in order to cover

the whole time of the manufacturing process that the API is in the liquid form.

5.5.3. Other holding times [3] [45]

A maximum holding time between the end of filling and the beginning of terminal sterilization is generally

evaluated for products terminally sterilized. The aim of this holding time is to establish a maximum time

53

that the product can stay in its final container until being subjected to the appropriate terminal sterilization

process without an increase in bioburden.

For cold chain products, a maximum total time at room temperature should be established. This holding

time is usually calculated from the beginning of API addition to the preparation tank until the end of

inspection/labelling/packaging (at room temperature), in order to evaluate the maximum time that the

product can be exposed above the refrigeration conditions without affecting its quality.

5.6. Filtration

Filtration is the process by which particles are removed from the bulk solution by passing it through a

porous material (filter). When the filtration process also removes microorganisms from the solution it is

called sterilizing filtration. A sterilizing-grade filter has a 0.2 µm or smaller pore size. However, the

classification of a filter by pore size has limited value and, therefore, this measurement has been

replaced by defining the filter in terms of its bacterial retention. Typically, a sterilizing-grade filter is a

filter that retains 107 CFU of a standard test organism (e.g., Brevundimonas diminuta ATCC® 19146™) 1

per cm2 of effective filtration area (EFA) 2 under process conditions. [3] [46] [47] [48] [49]

Pharmaceutical-grade filters are available in several sizes, membranes and configurations: [3] [46] [47]

[49]

Membranes – Filter membranes are made up of different materials of construction with specific

pore ratings and chemistries, such as, nylon, PVDF, polyetersulfone and PTFE.

Sizes – The filter size is usually determined in terms of EFA, which influences the flow rate 3

and total throughput 4 (the larger the EFA, the higher the flow rate and the throughput).

Configurations – The most widely filter configurations used in the pharmaceutical industry are

the following: capsule filter (a self-contained filter device – refer to figure 15) and cartridge filter

(a filter device requiring a housing for use – refer to figure 16).

1 Brevundimonas diminuta ATCC® 19146™ is the most commonly used microorganism for demonstrating a filter’s

bacterial retention capability. It can be obtained in lyophilized form from the American Type Culture Collection (ATCC) and, after reconstitution, stocks can be maintained either refrigerated or frozen on appropriate media. 2 Effective filtration area is the total surface area of the filter available to the process fluid. 3 Flow rate is the volumetric rate of flow of a solution expressed in units of volume per time (e.g., L/min). 4 Filter throughput (or capacity) is the amount of solution that can be filtered through the EFA and is expressed as volume per membrane area.

54

Figure 15 – Capsule filter [49] Figure 16 – Cartridge filter and stainless steel housings [49]

Several issues may be related to the filtration process, such as, product losses by adsorption to the

filter, presence of leachables from the filter in the product and sterile filtration not being effective leading

to an increase in bioburden and to a non-sterile final product. To assure sterility and to guarantee that

the product quality is not negatively affected by the filtration process, the functionality of the filter should

be demonstrated by the filter manufacturer and by the filter user (i.e., the pharmaceutical company

responsible for the drug product manufacturing). Usually, qualification documentation provided by the

filter manufacturer is used to support performance qualification conducted by the filter user as part of

process validation, which is particularly critical for aseptically processed products. Sterile filtration

validation includes several elements but is usually achieved by focusing on bacterial retention,

extractables/leachables and compatibility (refer to figure 17). [3] [46] [47] [49]

Figure 17 – Eight elements of a sterile filtration validation [47] 5

5 ASTM F838 is the standard test method for determining bacterial retention of membrane filters utilized for liquid filtration.

ASTM F838. 5

55

5.6.1. Integrity testing [3] [46] [47] [48] [49]

Integrity testing is a physical test that can be correlated to bacterial retention and is a determinant of

compatibility. Integrity testing of sterilizing-grade filters must be demonstrated before and after filtration,

using non-destructive methods, in order to determine the presence of defects that may compromise the

retention capability of the filter without destroying it. Integrity testing before use monitors filter integrity

prior to batch processing, preventing use of a non-integral filter. Integrity testing after a batch has been

filtered can detect if the integrity of the filter has been compromised during the process. Integrity testing

is usually achieved by one of the following methods: bubble point test or forward flow test.

5.6.1.1. Bubble point test

Bubble point test is the most commonly used non-destructive integrity test. Bubble point is based on the

fact that liquid is held in the pores of the filter by surface tension and capillary forces. The minimum

pressure required to force liquid out of the pores is a measure of the pore diameter. A minimum bubble

point is usually established by the filter manufacturer and remains valid as long as the fluid, membrane

type, pore size and filtration temperature are unchanged.

Bubble point test can be performed with the actual drug product or with a standard fluid, typically water

for hydrophilic membranes or an alcohol/water mixture for hydrophobic membranes. The filter is wetted

with the appropriate test fluid and then the system is pressurized to about 80% of the expected bubble

point pressure (which is stated in the manufacturer's literature). Afterwards, the pressure is slowly

increased until rapid continuous bubbling is observed at the outlet. The pressure value obtained should

be equal or higher than the bubble point specification. A bubble point value lower than the specification

is an indication of one of the following:

fluid with different surface tension than the recommended test fluid;

integral filter but with incorrect pore size;

inappropriate test temperature;

membrane not completely wetted;

non-integral membrane.

5.6.1.2. Forward flow test (also known as diffusive flow test)

At differential gas pressures below the bubble point, gas molecules migrate through the water-filled

pores of a wetted membrane following Fick's Law of Diffusion. The gas diffusional flow rate for a filter is

proportional to the differential pressure and the total surface area of the filter. The forward flow test

provides a quantitative measurement in which a maximum flow limit is established by the filter

manufacturer at a test pressure lower than the minimum bubble point value (usually, the test pressure

is approximately 80% of the minimum bubble point). Forward flow test can be performed with the actual

drug product or with a standard fluid, typically water for hydrophilic membranes or an alcohol/water

mixture for hydrophobic membranes. The filter is wetted with the appropriate test fluid and then the

pressure is slowly increased on the upstream side of the filter to the recommended test pressure

56

provided by the manufacturer. It is important to allow the system to equilibrate prior to measuring the

gas flow at the outlet. A flow rate higher than the specification is an indication of one of the following:

liquid/gas combination different than the recommended fluids;

integral filter but with incorrect pore size;

inappropriate test temperature;

membrane not completely wetted;

inadequate stabilization time;

non-integral membrane.

5.6.2. Bacterial Retention [3] [46] [47] [48] [49]

Bacterial retention of a filter is qualified and validated by the filter manufacturer and then by the filter

user under process conditions. The aim of the bacterial retention validation study (also known as

bacterial challenge) is to have documented evidence demonstrating that the filtration process will

consistently remove a high level of a standard test organism, suspended within the actual drug product

or a surrogate fluid, under simulated worst-case process conditions of contact time, temperature,

pressure and/or flow rate 6.

Brevundimonas diminuta is the mainly used microorganism for bacterial challenge tests for 0.2 µm filters.

Nevertheless, other bacteria can be used provided that they are small enough to challenge the retentive

capability of the filter and that they simulate the smallest microorganism found in production. The size

of the test organism should be confirmed by demonstrating passage through a 0.45 µm rated membrane

as a positive control.

When it is not possible to inoculate the challenge organism into the product due to its bactericidal activity,

a surrogate fluid is used instead. This fluid should match the product as closely as possible in terms of

its physicochemical characteristics (e.g., viscosity, surface tension and pH), without adversely affecting

the test organism and a proper rationale should be provided to support the fluid selection. The surrogate

fluid is only used after the filter has been in contact with the product under worst-case process conditions

and has been flushed with a fluid, determined during the viability study, which will eliminate any traces

of product. The viability of the microorganism should be verified prior to performing the bacterial

challenge test by direct inoculation into the carrier fluid (product or surrogate) and the exposure time

chosen should equal or exceed the actual process filtration time.

5.6.3. Extractables/leachables [3] [46] [47] [48] [49]

It is important to ensure that the filter does not adversely affect the product. Extractables are chemical

compounds that can be extracted from product contacting surfaces when exposed to an appropriate

solvent under exaggerated conditions (i.e., time and temperature). Pre-treatment of the product

contacting surface, such as gamma irradiation or steam sterilization, may also increase the levels of

extractables present. Assessment of extractables that may be introduced during pharmaceutical

6 It may not be possible to mimic pressure differential and flow rate simultaneously during validation and, therefore, the filter user should determine which parameter is more relevant to the process and provide proper rationale to support the decision.

57

manufacturing is an important consideration in evaluating the suitability of a process and its equipment

(including filters) for a particular application. The presence of extractables may be related to degradation

of the filter components ultimately affecting its ability to perform as intended. The quantity and

composition of extractables should be considered when determining the suitability of the filter for the

intended application. Flushing the filter prior to use may reduce the level of extractables potentially

entering the process stream. Extractables studies are usually conducted by the filter manufacturer using

model solvents that bracket the properties of pH, ionic strength and/or level of organic components of

the actual drug product. These studies should be performed with the entire filter device under specific

laboratory conditions that simulate worst-case process conditions of contact time, temperature and pre-

treatment (e.g., sterilization of the filter). The level of extractables is proportional to the effective filtration

area and, therefore, the test filter can have the same effective filtration area or higher than the filter to

be used during actual production. Leachables are compounds that migrate from the filter material in the

presence of the actual product formulation under normal process operating conditions. The need for

leachables testing should be assessed on a case-by-case basis by the filter user and, if applicable,

potential leachables are identified and evaluated to ensure they do not compromise the product quality.

5.6.4. Compatibility [3] [46] [47] [48] [49]

Chemical compatibility between the filter and the product can be qualified by the filter manufacturer.

However, filter user testing is required to confirm the compatibility of the product with the filter under

process conditions. Chemical compatibility should include the entire device and depends on the fluid,

filtration temperature and contact time. After product exposure, integrity testing must be performed on

the filter to verify if its integrity was compromised. Additionally, the filter should be visually inspected for

any signs of discoloration, distortion or damage to ensure that no observable physical change occurred.

5.6.5. Binding [3] [46] [47] [48] [49]

Adsorption is a mechanism of product binding to the filter materials (i.e., filter membrane and/or support

materials). It may lead to the loss of API and/or certain excipients that have an affinity for the filter

materials, having an impact on the product composition and concentration. The level of adsorption can

be affected by several factors, such as, product concentration, contact time, flow rate, temperature and

pH. This issue can be solved by selecting a filter with an appropriate composition and compatible with

the product formulation.

5.6.6. Sterilization 7 [3] [46] [47] [48] [49]

The sterility of the filtration assembly is one of the main elements of a successful sterilizing filtration

process. However, the sterilization method used may lead to damage if filters are not properly sterilized.

Therefore, the capability of the filter to be sterilized and sterilization conditions must be qualified by the

7 In a sterilization process, microbiological death or reduction is described by an exponential function. Therefore, the number of microorganisms that withstand a sterilization process can be expressed in terms of probability (which can be reduced to a very low number but can never be reduced to zero).

58

filter manufacturer. The filter user should sterilize the filters according to the manufacturer’s

recommendation and is responsible for validating the sterilization method selected (except gamma-

irradiated filters, which are generally sterilized by the filter manufacturer using validated conditions).

Sterilization of filters is typically performed by one of the following methods: steam sterilization or

irradiation sterilization. The most common sterilization method is steam under pressure, which is usually

performed in an autoclave, at a temperature of 121ºC. Steam sterilization validation should demonstrate

that the sterilization cycle leads to a probability of non-sterility equal to or lower than 10-6. Irradiation

sterilization is a method that can be used as an alternative to steam sterilization. It has several

advantages, such as, high sterility assurance level, no residual sterilization components (water) and,

consequently, dry filters. Since gamma-irradiated filters do not contain any residual water, they are

particularly advantageous for the filtration of non-aqueous products.

Generally, a maximum filtration time is established for each product/process based on the contact time

between the filter and the product evaluated during validation studies (bacterial retention, extractables

and compatibility studies).

Once a specific filter is validated for use in a certain process, further validation (i.e., revalidation) is

required only when some changes are made, such as:

Modifications regarding the drug product formulation, including product concentration, pH,

conductivity or viscosity;

Increase in the amount (volume) of bulk solution to be filtered through a given effective filtration

area;

Filtration temperature;

Sterilization method modifications;

Flow rate and/or pressure used during filtration.

The filtration process may also have some influence on the assay and pH of the bulk product, which is

typically evaluated during process performance qualification, as part of dead volume evaluation or filter

conditioning. Dead volume or filter conditioning is translated in the amount of bulk solution that needs

to be discarded prior to the start of filling in order to obtain a product within specifications. Typically, the

evaluation involves the testing of the first units filled (dead volume), which should be sequentially

numbered when they are collected, or the testing of a sample of bulk product collected immediately after

the filter at determined contacted times, in order to determine the amount of bulk solution to be rejected

prior to the start of filling, if any. Dead volume and filter conditioning time evaluation is typically performed

in the first PPQ batch manufactured, in order to establish an appropriate amount to be discarded in the

subsequent produced batches.

The assay and pH of the first units filled may be affected by the filtration process, particularly in the case

of online filtration (i.e., when filtration and filling occur simultaneously instead of the whole bulk solution

being previously filtered to a holding tank). If steam sterilized filters are not properly dried prior to use,

59

the first units filled may have lower assay results and/or higher pH due to the residual water that

remained in the filtration assembly. The use of an inappropriate drying procedure is particularly critical

for filters with a higher EFA, since a larger amount of water may remain in the filter. In this case, a high

amount of product has to be discarded as part of initial set up activities (i.e., prior to start actually filling),

which leads to excessive product losses. In order to avoid this situation, adequate drying procedures

should be qualified and validated for each filter or, as an alternative, the use of gamma-irradiated filters

may be considered.

5.7. Filling

Filling is the process of bringing the product in its final container. The effects of the filling process on the

product quality should be evaluated by analyzing samples collected at different time points (usually,

beginning, middle and end) considered representative of the whole filling process and after machine

stoppages. The filling uniformity can be affected by the characteristics of the product, which may

influence the dosing system (for instance, more viscous products can be more difficult to fill leading to

fill volume discrepancies). Therefore, the filling process has to be validated to assure that the filling

machine is accurate and that the pumps and needles used are adequate for each product. Usually, the

filling pumps and needles are selected based on the fill volume and the physical characteristics of the

product (particularly, viscosity). [3]

The filling process is directly related to the filling line. If a product is produced in more than one filling

line, the filling process should be validated in all of them. The effect of line stoppages on the product

quality should be evaluated in order to assess eventual unintentional stoppages that might occur during

the filling process (which may be particularly relevant in the case of products sensitive to oxygen and

viscous products). A line stoppage with appropriate duration (e.g., one or two hours) is usually

incorporated into the filling of one PPQ batch and the first units collected after the line stoppage are

analyzed to evaluate its impact on the product quality. The duration of the line stoppage should be

enough to allow proper intervention and resolution of eventual mechanical problems but without having

an impact on the product quality. [3]

5.8. Lyophilization (if applicable)

When a lyophilized product is to be manufactured, an appropriate lyophilization cycle should be

developed. Cycle development is done during the R&D phase however adjustments in cycle times and

parameters may occur when transferring from an R&D lyophilizer to an industrial lyophilizer. Therefore,

manufacturing of engineering / test batches is advisable before production of the PPQ batches. [3] [11]

60

Lyophilization involves heat and mass transfer, which must be taken into consideration for process

design and optimization, since these phenomena vary according to lyophilizer load condition (partial or

full load), lyophilizer design and container closure system. Monitoring and control of CPPs, such as,

shelf temperature and chamber pressure, is essential to achieve proper process control and to obtain a

cake with the desired appearance and quality (refer to figure 18). [3] [11]

Figure 18 – Appearance of a parenteral product before and after lyophilization [50]

During primary drying, it is crucial to maintain the temperature below the critical temperature, which is

the collapse temperature for amorphous solutes or the eutectic temperature for crystalline solutes.

Drying above the critical temperature leads to loss of cake structure (collapse or meltback), which can

ultimately results in rejection of the entire batch. [3] [11]

An example of a lyophilization cycle for an injectable pharmaceutical product is presented in table 7.

Table 7 – Example of a lyophilization cycle for an injectable product

Process phase Time (h:min) Shelf temperature Chamber pressure

(vacuum)

Loading 00:10 5 ºC -

Freezing 06:00 - 45 ºC -

Vacuum preparation 01:00 - 45 ºC 0.1 mbar

Primary drying 30:30 - 5 ºC 0.1 mbar

Secondary drying 02:00 40 ºC 0.1 mbar

Total cycle time 39:40 (h:min)

Freeze drying is typically an expensive and time-consuming process. Therefore, it is usual to try to

improve the process by reducing the cycle time, focusing particularly on optimization of the primary

drying phase, which is the longest of all the three phases. Once a lyophilization cycle is developed and

optimized, process performance qualification is performed as part of process validation in order to

demonstrate that the lyophilization process allows obtaining a product within specifications. The

uniformity and efficiency of the lyophilization process is evaluated by collecting samples from several

positions of the lyophilizer, which are usually tested for cake appearance, reconstitution time and water

content. Evaluation of the lyophilization process is important not only to assure uniform product quality

within the batch but also from batch to batch. [3] [11]

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5.9. Terminal sterilization (if applicable)

Terminal sterilization is a process whereby the product is sterilized within its final container. This process

is typically used for heat-stable products and is usually accomplished by moist heat sterilization (in an

autoclave). The efficacy of the sterilization process is dependent on heat exposure, number of

microorganisms present in the load (bioburden) and heat resistance of those microorganisms.

Sterilization must lead to a SAL 8 of at least 10-6 (less than one non-sterile unit per one million units).

The determination of the sterilization method to be used for product sterilization (moist heat sterilization

or aseptic filling) is done during R&D stage. Sterilization in the final container is the preferred sterilization

method which is considered to provide a great assurance of sterility. [3] [33] [51] [52]

5.9.1. Terminal sterilization process development and qualification [3] [33] [51] [52]

Two main design approaches are used for the development of moist heat sterilization cycles to be

applied in pharmaceutical manufacturing: overkill approach or product-specific approach. Usually, the

design approach is selected based on the thermal stability of the product and the materials to be

sterilized. The overkill design approach requires less information on the bioburden of the items to be

sterilized than the product-specific design approach. A greater heat input is required, which has a greater

potential to degrade the product and materials subject to sterilization. Therefore, this approach is

normally employed to products and materials that can withstand high heat without affecting their quality.

On the other hand, the product-specific design approach requires a greater amount of information

regarding the items to be sterilized, the indicator organisms (the test organisms shown to be most

resistant to the sterilization process) and the bioburden levels than the overkill approach. Gathering all

this information provides confidence in the values determined in development to use a lower thermal

input than required for the overkill design approach. This is advantageous for the terminal sterilization

of products that cannot withstand the higher temperatures required for the overkill approach, which

provides greater stability and potentially increases the shelf-life of these products.

A survivor curve is a graphical representation of the inactivation or death of a population of

microorganisms exposed to certain lethal conditions and is described using the following semi-

logarithmic equation:

log 𝑁𝐹 =−𝐹(𝑇,𝑧)

𝐷𝑇+ log 𝑁0 Equation 4

Where,

NF – Number of microorganisms after exposure of F equivalent minutes

F(T,z) (Lethality factor: F-value) – equivalent lethality of a cycle, calculated as minutes at a

reference temperature (T), using a defined temperature coefficient (z); it is a measurement of

8 Sterility Assurance Level expresses the probability of occurrence of a non-sterile unit after exposure to a sterilization process.

62

the sterilization cycle effectiveness. z-value is the number of degrees of temperature change

necessary to change the D-value by a factor of 10.

DT (Thermal resistance value: D-value) – Time, in minutes, required for a one-logarithm (or

90%) reduction of the population of microorganisms used as a biological indicator at a specified

temperature (T).

N0 – Number of microorganisms prior to exposure

The terminal sterilization process should be properly qualified in order to ensure that it consistently

meets the design criteria determined for the cycle. Qualification must include both physical and biological

qualification. Biological qualification demonstrates, by use of biological indicators, that the required

lethality (FBIO) is achieved consistently through the load. FBIO is a term used to describe the delivered

lethality measured in terms of actual kill of microorganisms. The most common microorganism used as

a biological indicator is Geobacillus stearothermophilus due to its high heat resistance but other resistant

bacteria may be acceptable. Nevertheless, the biological indicator selected should contain a higher

population and resistance than the expected product bioburden and only spores should be used as

microbiological challenges. Physical qualification demonstrates that predetermined physical

requirements, including sterilization temperature and time, minimum F0 9 and minimum exposure time,

are achieved consistently from load to load. Three maximum loads and three minimum loads have to

be validated per product. FPHYS is a term used to describe the delivered lethality calculated based on the

physical operational parameters of the cycle, which is the integration of the lethal rate over time.

Physical attributes of the drug product, such as, container size, fill volume, mass and physical

configuration may affect temperature distribution 10, heat penetration 11 and microbiological inactivation.

Therefore, it is crucial that temperature distribution and heat penetration studies are performed for each

sterilization process and load pattern (number of containers per tray and number of trays in the load).

Adequate operational parameters must be established for the sterilization process to ensure that the

required physical and biological lethality are achieved while maintaining integrity of the container closure

system and product quality. These parameters consist of a set point and an operating range, which

should be carefully evaluated since the lower end of the range can affect the sterilization process

efficacy and the upper end may affect the product stability.

5.9.2. Relationship between process validation and parametric release of pharmaceutical products (only

applicable to terminally sterilized products) [3] [33] [53]

Process performance qualification is performed as part of process validation in order to demonstrate

that the terminal sterilization process allow obtaining a product within specifications, not only in terms of

9 F0 is the number of equivalent minutes of moist heat sterilization at a temperature of 121ºC delivered to a unit of product. This is calculated using a z-value of 10ºC. If, for instance, a cycle has a stated F0 of 8 minutes, then the sterilization effectiveness of that cycle is equivalent to 8 minutes at 121ºC. 10 Temperature measurement of the heating medium across the autoclave chamber load zone. 11 Temperature measurement that is used to evaluate the amount of thermal energy that has been transferred to the materials that are to be sterilized within the load.

63

sterility but also regarding its physicochemical attributes. Usually, for terminally sterilized products, it is

recommended to evaluate the effects of double terminal sterilization as a worst-case scenario, in order

to determine if the product can withstand two sterilization cycles without affecting its quality.

Parametric release is a system of release that provides sterility assurance based on effective control,

monitoring and documentation as well as a thorough understanding gained during the manufacturing

process validation rather than finished product sterility testing. CPPs that are considered critical for

sterility assurance should be identified for the sterile product manufacturing process. Once identified,

these parameters are properly monitored and controlled, leading to a predictable and reproducible

process. Time, temperature and pressure are examples of critical parameters that must be closely

monitored and controlled during the sterilization cycle, in order to ensure the sterility of the finished

product.

Sterility test is limited in its sensitivity and lacks statistical significance for the evaluation of sterility for

terminally sterilized products due to the low probability of detection of contaminated units. Like all

destructive testing, it is not possible to prove that a batch of product is sterile unless the entire lot is

tested. Additionally, microbiological results are not available in real-time and physical measurements

are used to provide verification of the achievement of operational parameters after cycle completion.

Therefore, sterility assurance should be established through execution of a well-designed and validated

sterilization process instead of being tested into the product.

A parametric release program is usually applicable to pharmaceutical products terminally sterilized by

moist heat due to the following reasons:

It is a well understood and reliable process;

It can be easily controlled and validated;

It is effective against several types of microorganisms (such as, molds, yeasts and

bacteria/spores);

Lethality can be mathematically modeled.

A parametric release program can be used for new and existing products or processes but in both cases

a well justified risk assessment should be developed to preclude the potential to manufacture and

release a non-sterile product.

Proper monitoring and control of pre-sterilization bioburden should be conducted to support sterility

assurance of products that are parametrically released. Limits for product bioburden should be

established, which allow adopting the proper corrective actions whenever negative trends are detected

and ensure that the sterilization process efficacy is not compromised by an unacceptable level and/or

resistance of pre-sterilization bioburden. The load is considered non-sterile if the pre-sterilization

bioburden and/or resistance are greater than the biological indicator challenge used in validation (which

is particularly relevant for sterilization processes designed based on product-specific design approach).

64

Once a sterilization cycle is qualified and validated, load release should be based on meeting

sterilization specifications, as follows:

Product bioburden is within specifications;

The autoclave and all instrumentation used was properly qualified and calibrated;

The validated load pattern was used;

CPPs have been achieved (failure to meet CPPs leads to rejection of the load).

5.10. Inspection

All finished product batches should be 100% inspected in order to verify the level of rejects due to

particles and/or defects (liquid products are inspected for particles and defects while lyophilized products

are only inspected for defects). The inspection results can be used to specify a tentative rejection rate

and they are extremely useful if properly evaluated since the rejected units might be related to the

process or to the product itself. When a particular type of particle or defect appears often, an

investigation should be conducted in order to understand if it is associated with any issue related to the

process or to the product formulation. Once the root cause is identified, proper corrective measures can

be established in order to decrease the number of defective units. [3]

Finished product units should be also subjected to non-destructive leak testing, in order to confirm the

integrity of the container closure system. One of the most commonly used methods is high voltage leak

detection, which ensures product seal integrity by identifying small pinholes, cracks and seal

imperfections that cannot be detected by visual inspection. [3]

5.11. Scale-up and scale-down considerations

When there is the intention to change the validated batch size of a certain product, several aspects need

to be taken into consideration to evaluate its feasibility. Both scale-up or scale-down can be considered

for existing products, usually due to changes in market demand or line transfer. [3]

For new products, scale-up can be done based on submission batches of a specific product

manufactured in a specific line. Adopting a systematic approach might be useful to determine the

proposed scale-up batch size based on pilot-scale batches previously manufactured for submission or

process validation purposes, for instance, by schematizing all data available in a table (refer to table 8

as an example). This is particularly useful for products intended to be commercialized in the US market,

since a proposed batch size is selected based on the data obtained from the batches manufactured for

submission purposes. In this case, any batch size between the batch size of the submission batches

manufactured and the approved proposed batch size can be considered for commercial production. The

batch size of the submission batches should be at least 10% of the proposed maximum size commercial

65

batch, 50 L (per batch if the fill volume per container is larger than 2.0 mL) or 30 L (per batch if the fill

volume per container is up to 2.0 mL), whichever is larger. For products intended to be commercialized

in the European market, the approved batch size is equivalent to the batch size of the batches

manufactured for submission purposes. [3]

5.11.1. Compounding [3] [25]

The availability of tanks of a higher capacity adequate for the new batch size should be ensured. The

amount of API and excipients required for the new batch size should be taken into consideration. For

instance, the possibility of adding large amounts of a raw material to the tank should be properly

evaluated before the scale-up is done.

For products that require pH adjustment, it might be important to calculate the estimated amount of pH

adjustment solutions needed for the new batch size.

5.11.2. Holding times, filtration and filling [3]

The holding times are evaluated and established for the product regardless of the batch size and,

therefore, should not be changed when a scale-up is done. They may be confirmed however during

validation of the new batch size.

It should be evaluated if a filter with an effective filtration area adequate to the new batch size is

available. If not, multiple filters may be used however the impact of this change should be evaluate in

terms of process and filter validation studies. The effective filtration area required to filter a certain

volume is usually determined by small-scale filterability studies. Either constant flow or constant

pressure filterability tests can be used to predict manufacturing performance. The majority of the

filterability tests are performed by keeping pressure constant and measuring the decline in flow rate as

a function of the filtered volume. In this case, the pressure used should mimic production pressure

conditions. Regarding constant flow testing, the flow rate is controlled while the pressure gradually

increases until a maximum pressure is reached.

The output of the filling line should be considered to calculate the expected filling duration for the new

batch size. The expected filling duration should be covered by the maximum filling time qualified by

Media Fill. In case of online filtration, the expected filling duration should also be covered by the

maximum contact time of the filter with the product, since the filtration and filling occur simultaneously

and, therefore, their duration is almost the same (available filter validation studies should be evaluated).

The product should also be compatible with the remaining product contact materials (for instance, tubing

and gaskets), during the expected filling time. If there are no studies available to cover such duration, a

decision should be made to determine if a surfaces compatibility study is required to be done prior to

production or if compatibility will be assessed during production of the first scale-up batch (applicable

when the risk is considered to be low).

66

5.11.3. Process validation requirements [3]

New process performance qualification studies need to be performed due to the increase in the batch

size. The following parameters usually have to be re-evaluated during process validation:

evaluation of the quality of the bulk solution by taking samples from the top and bottom of the

compounding tank for physicochemical testing and bottom sample for bioburden testing –

although the drug product formulation is the same, the batch size and the tank to be used are

different;

the bulk holding time should be confirmed in the new tank – although the material of construction

is the same, a tank with a higher capacity is considered a worst-case for bioburden growth and

for products sensitive to oxygen if the tank headspace is higher;

evaluation of the effects of filtration and filling on the quality of the compounded solution by

taking samples in the beginning, middle and end of filling (although the drug product formulation

and the fill volume are the same, the filtration and filling duration will be longer for the scale-up

batches);

evaluation of finished product results by taking representative samples of the batch after

lyophilization or terminal sterilization, if applicable.

5.11.4. Other considerations [3] [25]

Before the scale-up protocol is designed, the available data for the current batch size needs to be

evaluated, particularly the existence of previous deviations or non-conformities, in order to understand

if there is any issue related to the process or to the product itself that needs to be solved or improved

before the scale-up is done.

The capacity of all equipment must be considered when evaluating scale-up feasibility. For instance, for

lyophilized products, the scale-up batch size should be adjusted to the lyophilizer capacity (minimum

and maximum load) and condenser capacity.

67

Table 8 – Example of a schematic approach for presenting a rationale for submission of a proposed scale-up

batch size of a specific product in a specific filling line

Product presentation 5 mL presentation 10 mL presentation 25 mL presentation

Batch number * XXXXX1 XXXXX2 XXXXX3

Batch size * 50 L 100 L 250 L

Theoretical number of vials * 9259 vials 9345 vials 9652 vials

Viable vials (after 100 % inspection, including samples for quality control) *

8610 vials 8410 vials 9169 vials

Batch average volume * 5.41 mL 10.69 mL 25.92 mL

Yield *

[Yield (%) = (Viable vials / Theoretical number of vials) x 100]

93 % 90 % 95 %

Theoretical proposed maximum batch size

(Theoretical proposed batch size for US Market = Viable vials x Batch average

volume x 10)

465 L 899 L 2376 L

Proposed batch size 465 L

500 L

(Although theoretically it is possible to have bigger batch sizes, due to the available

equipment, the proposed batch size cannot exceed 500 L.)

Target fill volume 5.40 mL 10.70 mL 25.90 mL

Theoretical output

(according to the vial size)

15000 vials/hour for 6 mL vials

10000 vials/hour for 10 mL vials

6000 vials/hour for 25 mL vials

Number of vials of the proposed batch size

(based on the target fill volume)

86111 vials 46728 vials 19305 vials

Approximately filling duration for the proposed batch size

05 h 44 min 04 h 40 min 03 h 13 min

Maximum filling time qualified by Media Fill

24 h 30 min

* Data from the submission batches already manufactured for the product.

68

5.12. Stability studies

After manufacturing, samples from all process validation batches should be placed in stability chambers.

The purpose of stability studies is to provide evidence on how the quality of a drug product varies with

time under the influence of different environmental factors (e.g., temperature and humidity) and to

establish a proposed shelf-life or confirm the shelf-life for the drug product and the recommended

storage conditions. [3] [54] [55]

The design of the stability studies for the drug product should be based on knowledge of the

characteristics of the drug substance, from stability studies on the drug substance and on experience

gained from earlier phases of pharmaceutical development. Generally, a drug product should be

evaluated under storage conditions that test its thermal stability and its sensitivity to moisture or potential

for solvent loss, if applicable. Data from stability studies should be provided on at least three batches of

the drug product, which should have exactly the same formulation, packaged in the same container

closure system and produced using the same manufacturing process as proposed for commercial

batches. Preferably, all batches used for process validation purposes should enter stability studies. [3]

[54] [55]

Specific types of stability studies may be performed on at least one batch of the drug product, such as,

photostability and freeze thaw studies. The photostability characteristics of new drug products should

be evaluated to demonstrate that light exposure does not result in unacceptable change. This evaluation

should allow to clearly define if the product is photostable or photolabile. If the results of the study are

equivocal, testing of one or two additional batches should be conducted. Usually, photostability studies

are carried out in a sequential manner starting with testing the directly exposed drug product and,

afterwards, continuing as necessary to the product in the primary packaging and then in the secondary

packaging. This evaluation should progress until the results demonstrate that the drug product is

adequately protected from light exposure. Freeze thaw studies are performed to predict the impact of

temperature excursions 12 on the drug product quality during the transportation / distribution process.

These studies are done by placing samples of the drug product at extreme temperatures (i.e., samples

are exposed at freezing temperatures followed by exposure at accelerated storage conditions) to

evaluate if the product is stable after cycles of temperature excursions. [3] [56] [45]

A stability protocol needs to be issued for each drug product. The stability protocol defines the number

of samples needed, the storage conditions to be followed, the sample storage orientation (upright or

inverted), the testing points, the tests to be performed and the drug product shelf-life specifications.

Stability studies should include testing of those attributes of the drug product that are susceptible to

change during storage and are expected to influence quality, safety and/or efficacy. The testing should

cover, as appropriate, the physical, chemical and microbiological attributes, preservative content

12 Any event in which the product is exposed to temperatures outside of the recommended storage and/or transportation temperature range.

69

(antioxidant or antimicrobial preservative) and functionality tests (for instance, for a dose delivery system

or multidose vial). [3] [54] [55]

Usually, a stability study should start not more than 30 days after the end of manufacturing. When this

is not possible and samples only enter stability after 30 days, a new time zero testing will be performed.

In case samples enter stability within the defined period, time zero corresponds to release testing date.

Several stability chambers with different storage conditions of temperature and relative humidity (RH)

can be used to perform these studies (refer to table 9), according to the container closure system,

product storage conditions and the climatic conditions of the target markets (refer to table 10). [3] [54]

[55]

Table 9 – Stability storage conditions and study duration per type of stability study

Stability study Storage conditions Study duration

Long-term

25ºC ± 2ºC / 60% ± 5% RH

Until the end of shelf-life

25ºC ± 2ºC / 40% ± 5% RH

30°C ± 2°C / 35% ± 5% RH

30ºC ± 2ºC / 65% ± 5% RH

30ºC ± 2ºC / 75% ± 5% RH

5ºC ± 3ºC

- 20°C ± 5°C

Intermediate 30ºC ± 2ºC / 65% ± 5% RH 12 months

Accelerated

40ºC ± 2ºC / 75% ± 5% RH

6 months 40ºC ± 2ºC / ≤ 25% RH

25ºC ± 2ºC / 60% ± 5% RH

Table 10 – Climatic zones. Adapted from [55]

Climatic zone Definition Mean annual temperature / mean annual partial water

vapor pressure

Proposed long-term stability testing

conditions

I Temperate climate ≤ 15ºC / ≤ 11 hPa 21ºC / 45% RH 1

II Subtropical and Mediterranean

climate 15 – 22ºC / 11 – 18 hPa 25ºC / 60%RH

III Hot and dry climate > 22ºC / ≤ 15 hPa 30ºC / 35% RH 2

IVa Hot and humid climate > 22ºC / 15 – 27 hPa 30ºC / 65% RH

IVb Hot and very humid climate > 22ºC / > 27 hPa 30ºC / 75% RH

1 Usually, when it is intended to market products in temperate climates, it is recommended that stability studies

should be based on the conditions corresponding to climatic zone II.

2 For countries where certain regions are situated in zones III or IV, and also with a view to the global market, it is

recommended that stability studies should be based on the conditions corresponding to climatic zone IV.

The frequency of testing selected for long-term studies should be sufficient to establish the stability

profile of the drug product. For products with a proposed shelf-life of at least 12 months, the frequency

70

of testing at long-term storage conditions should normally be every three months over the first year,

every six months over the second year and annually afterwards through the proposed shelf-life.

Regarding accelerated storage conditions, a minimum of three time points, including the initial and final

time points (e.g., 0, 3, and 6 months) from a six-month study is recommended. When intermediate

studies are required as a consequence of a significant change at accelerated storage conditions, a

minimum of four time points, including the initial and final time points (e.g., 0, 6, 9, 12 months) from a

12-month study is recommended. [3] [54] [55]

The long-term testing should cover a minimum of six or 12 months at the time of submission and should

be continued for a period of time sufficient to cover the proposed shelf-life. If no significant change is

observed in the drug product stability at six months’ testing at accelerated conditions, the proposed

shelf-life is usually based on data available from accelerated studies and data covering a minimum of

six months may be submitted. For drug products intended to be stored in a refrigerator or in a freezer,

the proposed shelf-life is usually based on the real-time data available from long-term studies and data

covering a minimum of 12 months should be submitted. [3] [54] [55]

5.12.1. General case

Table 11 – Stability storage conditions (general case). Adapted from [55]

Stability study Storage conditions Minimum time period covered

by data at submission

Long-term 1

25°C ± 2°C / 60% ± 5% RH or

30°C ± 2°C / 65% ± 5% RH or

30°C ± 2°C / 75% ± 5% RH

12 months or 6 months

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

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

1 The storage conditions selected for long-term stability studies are determined by the climatic zone(s) in which the

drug product is intended to be marketed. Testing at a more severe long-term condition can be an alternative to

storage at 25°C ± 2°C / 60% ± 5% RH or 30°C ± 2°C / 65% ± 5% RH.

2 If 30°C ± 2°C / 65% ± 5% RH or 30°C ± 2°C / 75% ± 5% RH is the long-term condition, there is no intermediate

condition.

Regarding long-term studies conducted at 25°C ± 2°C / 60% ± 5% RH, if a significant change occurs at

any time during 6 months’ testing at accelerated storage conditions, additional testing at intermediate

storage conditions should be conducted and properly evaluated. A significant change for a drug product

is generally defined as: [3] [54] [55]

a 5% change in assay from its initial value;

any degradation product / impurity exceeding its acceptance criteria;

failure to meet the acceptance criteria for appearance, physical attributes and functionality test,

if applicable;

failure to meet the acceptance criteria for pH.

71

5.12.2. Drug products packaged in impermeable containers

Regarding drug products packaged in impermeable containers (e.g., glass ampoules), sensitivity to

moisture or potential for solvent loss is not a concern since the containers provide a permanent barrier

to passage of moisture or solvent. Therefore, stability studies for these products can be conducted under

any humidity condition and only the temperature has to be controlled. [3] [54] [55]

5.12.3. Drug products packaged in semi-permeable containers

In addition to physical, chemical and microbiological stability, aqueous-based products packaged in

semi-permeable containers (e.g., bags) should be evaluated for potential water loss. This evaluation

should be done under conditions of low relative humidity, in order to demonstrate that aqueous-based

drug products stored in semi-permeable containers can withstand low relative humidity environments

(refer to table 12). [3] [54] [55]

Table 12 – Stability storage conditions (drug products stored in semi-permeable containers). Adapted from [55]

Stability study Storage conditions Minimum time period covered

by data at submission

Long-term 1 25°C ± 2°C / 40% ± 5% RH or

30°C ± 2°C / 35% ± 5% RH 12 months

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

Accelerated 40°C ± 2°C / ≤ 25% RH 6 months

1 The storage conditions selected for long-term stability studies are determined by the climatic zone(s) in which the

drug product is intended to be marketed. Testing at 30°C ± 2°C / 35% ± 5% RH can be an alternative to storage at

25°C ± 2°C / 40% ± 5% RH.

2 If 30°C ± 2°C / 35% ± 5% RH is the long-term condition, there is no intermediate condition.

For long-term studies conducted at 25°C ± 2°C / 40% ± 5% RH, additional testing at intermediate storage

conditions should be performed to evaluate the temperature effect at 30°C if a significant change (other

than water loss) occurs during accelerated studies. Intermediate studies are not required if only a

significant change in water loss occurs at accelerated storage conditions. Nevertheless, data should be

provided to demonstrate that the drug product will not have significant water loss throughout the

proposed shelf-life if stored at 25°C and relative humidity of 40% RH. A 5% loss in water from its initial

value is considered a significant change for a product packaged in a semi-permeable container after an

equivalent of 3 months’ storage at accelerated conditions (40°C / ≤ 25% RH). [3] [54] [55]

72

5.12.4. Drug products intended for storage in a refrigerator

Table 13 – Stability storage conditions (drug products intended for storage in a refrigerator). Adapted from [55]

Stability study Storage conditions Minimum time period covered

by data at submission

Long-term 5°C ± 3°C 12 months

Accelerated 1

25°C ± 2°C / 60% ± 5% RH or

30°C ± 2°C / 65% ± 5% RH or

30°C ± 2°C / 75% ± 5% RH

6 months

1 The storage conditions selected for accelerated stability studies are based on a risk assessment approach. Testing

at a more severe accelerated condition can be an alternative to storage at 25°C ± 2°C / 60% ± 5% RH or 30°C ±

2°C / 65% ± 5% RH.

If a significant change occurs between three and six months’ testing at accelerated storage conditions,

the proposed shelf-life should be based on the real-time data available from long-term studies. If a

significant change occurs within the first three months’ testing at accelerated storage conditions, an

evaluation should be made to address the effect of short term excursions outside the label storage

condition. It can be supported, if appropriate, by further testing on a single batch of the drug product for

less than three months but with more frequent testing than usual. Whenever a significant change occurs

within the first three months, there is no need to continue accelerated studies through six months. [3]

[54] [55]

5.12.5. Drug products intended for storage in a freezer

Table 14 – Stability storage conditions (drug products intended for storage in a freezer). Adapted from [55]

Stability study Storage conditions Minimum time period covered

by data at submission

Long-term - 20°C ± 5°C 12 months

For drug products intended for storage in a freezer, the shelf-life should be based on the real-time data

obtained at long-term storage conditions. The effect of short term excursions outside the proposed label

storage condition should be addressed by evaluating one batch at an elevated temperature (e.g., 5°C ±

3°C or 25°C ± 2°C) for an appropriate time period. [3] [54] [55]

73

6. CONCLUSION

All pharmaceutical products undergo several stages prior to start being routinely manufactured for

commercial purposes. During pharmaceutical development, the product and the related manufacturing

process are designed in order to deliver the intended performance and meet the needs of patients and

healthcare professionals and regulatory authorities’ requirements.

Once a product and a process are developed, several technical aspects need to be evaluated and

numerous activities need to be performed to ensure that the process performs reproducibly and

consistently delivers a product with the desired quality. Technology transfer follows pharmaceutical

development and involves transfer of product and process knowledge to achieve product realization. It

includes all the activities required for successful progress from pharmaceutical development (R&D) to

production (for new products) or from one manufacturing site to another (for marketed products).

Process validation is part of technology transfer and is used to demonstrate that the manufacturing

process developed, operated within established parameters, can consistently deliver the intended

product. A proper correlation between process inputs (CMAs and CPPs), their associated manufacturing

controls and process outputs (CQAs) is crucial to successful process validation. Since there are several

inputs, outputs and controls associated with each manufacturing operation, a systematic approach that

emphasizes product and process understanding, based on quality risk management, is crucial to identify

and to evaluate the process validation activities to be performed during technology transfer.

Nevertheless, it is important to recognize that process validation is not an isolated event and should

occur throughout the lifecycle of the product, in order to assure that the manufacturing process is

continuously in a state of control and delivering consistently a product with the desired quality.

74

7. FUTURE PERSPECTIVES

The manufacture of injectable pharmaceutical products is particularly complex and each manufacturing

unit operation should be properly validated and controlled in order to assure obtaining a sterile drug

product. Any scientific / technological advancement should be considered as an opportunity to ease and

improve the process.

PAT is an advanced strategy that is extremely useful to provide a higher degree of process control,

since it allow real-time monitoring and control to adjust the processing conditions so that the output

remains constant. However, PAT tools are not being as extensively used as they could. Probably, in a

near future, these tools will start to be more and more used in the pharmaceutical industry, both for

process validation activities and routine process control.

The tendency should be to decrease sampling and off-line testing, which slows the manufacture and

validation activities of pharmaceutical products, particularly injectable products (which are complex per

se). Additionally, PAT can be used to ease and accelerate batch release, which ultimately leads to a

product entering the market much more quickly, which can represent an advantage over other

pharmaceutical companies that do not apply this technology.

75

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78

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79

9. APPENDICES

Appendix 1 – Decision tree for sterilization choices for aqueous products. Adapted from [10]

Can the product be sterilized

by moist heat at 121ºC for 15

minutes?

No Yes

Can the product be sterilized

by moist heat with F0 ≥ 8

minutes achieving SAL of ≤

10-6?

Use autoclaving at 121ºC for

15 minutes.

Yes

Use moist heat with F0 ≥ 8

minutes.

No

Can the formulation be

filtered through a microbial

retentive filter?

No

Use pre-sterilized individual

components and aseptic

compounding and filling.

Yes

Use a combination of aseptic

filtration and aseptic

processing.

80

Appendix 2 – Process mapping for a liquid injectable pharmaceutical product

Process Parameters Attributes of input materials Manufacturing process steps Quality attributes of output

Tank size/type

Compatible contact materials

Order of raw materials addition

Bulk solution temperature

Mixing time

Mixing speed

Lighting condition

Chemical stability of API and excipients

Process related impurities

Compounding

Bulk solution appearance

Bulk solution assay

Bulk solution pH

Bulk solution density

Bulk solution bioburden

Storage temperature

Storage time Bulk solution Storage of bulk solution

Bulk solution appearance

Bulk solution assay

Bulk solution pH

Bulk solution density

Bulk solution bioburden

Filter size/type

Filter integrity

Pressure

Filtration time

Bulk solution Filtration

Appearance of sterile filtered bulk solution

Assay of sterile filtered bulk

solution

Fill volume range

Compatible product contact materials

Filling machine speed

Lighting condition

Sterile filtered bulk solution

Sterilized vials

Sterilized stoppers

Filling / Closing Sterilized filled vials quality

Fill volume (IPC)

Storage conditions

Type of inspection

Stoppered, sealed,

sterilized vials

Inspection

Vial defects

Appearance

Identification

Assay

pH

Volume in container

Impurities

Residual solvents

Particulate matter

Bacterial endotoxins

Sterility

81

Appendix 3 – Process flowchart for a liquid injectable pharmaceutical product

Appendix 4 – Risk assessment regarding the manufacture of a liquid injectable pharmaceutical product (FMECA)

ID # Operation Potential failure mode Potential cause of

failure Potential effect of failure

Risk RPN

(SxOxD) Risk Evaluation

S O D

A Raw materials

weighing Incorrect amount of raw

materials. Human error or equipment

malfunction. OOS results leading to

batch rejection. 5 2 2 20

Low risk.

Weighing operation is double verified.

Scales are calibrated daily and undergo regular maintenance.

B API amount

calculation based on potency

Amount of API higher or lower than required.

Human error. Low or high assay results leading to batch rejection.

5 2 2 20

Low risk.

Calculation of the API amount to use is double verified before weighing and

recorded in the batch record.

C API dissolution

API not completely dissolved due to

insufficient mixing time and/or mixing speed.

Human error or equipment malfunction.

Low assay results leading to batch rejection.

5 3 3 45

Medium risk.

Mixing speeds and times to be evaluated during the manufacture of the PPQ

batches.

D Bulk solution temperature

API degradation or improper dissolution if

bulk solution temperature is outside

the required range (20 – 25 ºC).

Human error or temperature sensor

malfunction.

Low assay results and/or high impurities results

leading to batch rejection. 5 2 2 20

Low risk.

The compounding temperature is specified in the batch record. Calibrated temperature sensors are used to monitor

the temperature.

E pH measurement and adjustment

pH outside the required range.

Human error. pH meter not correctly calibrated.

OOS pH results leading to product degradation and

batch rejection. 5 4 2 40

Medium risk.

pH meters are calibrated daily and undergo regular maintenance. pH range is specified in the batch record and pH

measurements are double verified.

F Final Q.S. Incorrect final solution

weight. Human error or floor scale

malfunction. OOS assay results

leading to batch rejection. 5 3 2 30

Low risk.

The floor scale is calibrated daily and verified prior to each compounding

(double verification).

G Light protection Exposure of the bulk

solution to light. Human error.

Product degradation leading to OOS results

and batch rejection. 5 3 2 30

Low risk.

The use of yellow filters to protect the product from light is specified in the

batch record.

H Compounding time Excessive

compounding time.

Human error. Equipment malfunction can contribute

to exceed this holding time.

Degradation of the product, increase in

impurities and increase in bioburden leading to batch

rejection.

5 3 2 30

Low risk.

A maximum compounding time is to be evaluated and established after the manufacture of the PPQ batches. Solution is stored in a sealed tank.

83

ID # Operation Potential failure mode Potential cause of

failure Potential effect of failure

Risk RPN

(SxOxD) Risk Evaluation

S O D

I Sampling

Incompatibility with container surfaces.

Improper handling of samples.

Human error.

OOS results due to improper sampling leading

to erroneous batch rejection.

5 2 4 40

Medium risk.

Sampling procedures are described in standard operating procedures.

J Bulk Holding time

Excessive holding time from the end of

compounding to the end of filling.

Human error. Equipment malfunction can contribute to exceed the bulk holding

time.

Degradation of the product, increase in

impurities and increase in bioburden leading to batch

rejection.

5 4 3 60

High risk.

A maximum bulk holding time is to be evaluated and established after the manufacture of the PPQ batches.

K Sterile Filtration

Non-integral filter and/or incompatibility between

the product and the filter materials.

Human error (improper filter selection). Defective

filter received from the manufacturer.

OOS results and non-sterile product leading to

batch rejection. 5 2 2 20

Low risk.

New filters are used in each production and pre and post integrity tested. Sterile filtration validation studies are available

to support the use of the filter.

L Filling

Incompatibility between the product and its contact materials.

Improper selection of pumps and needles leading to volume

variation.

Human error (selection of materials not compatible

with the product, scale not properly calibrated).

Mechanical problems.

OOS IPC fill volume results and non-sterile

product leading to batch rejection.

5 2 4 40

Medium risk.

Equipment and materials are specified in the batch record. Scale is calibrated

daily. Line set up activities are double verified prior to production.

M Closing Vials not properly

closed.

Human error (selection of incompatible

components). Mechanical problems.

OOS sterility results due to non-integral vials

leading to batch rejection. 5 2 3 30

Low risk.

Container closure integrity demonstrated. Machinability tests are performed prior to

production.

N

Components sterilization (e.g., machine parts, vials, stoppers)

Non-sterile components due to improper

sterilization cycles.

Human error. Mechanical problems.

Non sterile product leading to batch rejection.

5 2 4 40

Medium risk.

Qualified cycles are used for each component sterilization. Probes

calibrated on annual basis

O

Physicochemical and microbiological

finished product testing

Finished product specifications not met.

Human error. Use of non-validated test methods.

OOS results leading to batch rejected.

5 3 2 30

Low risk.

Validated test methods are used. All results are documented and verified.

S – Severity: Level 1 (low) to 5 (high); O – Occurrence / Probability: Level 1 (rare) to 5 (frequent); D – Detectability: Level 1 (high) to 5 (low) RPN (SxOxD): 0 – 19: No risk 20 – 39: Low risk 40 – 59: Medium risk 60 – 100: High risk

84

Appendix 5 – Risk assessment regarding transfer of a liquid injectable pharmaceutical product between manufacturing sites (FMEA)

Process Step Item Current manufacturing site New manufacturing site Rationale for the change proposed Risk evaluation

Raw materials/

Components

API API from manufacturer “x” is used. API from manufacturer “x” will be used. N/A No risk.

API from the same manufacturer will be used.

Excipients Excipients from manufacturer “y” are

used. Excipients from manufacturer “z” will be

used.

As part of the Technology Transfer to the new manufacturing site, the excipients already available will be used in order to decrease the number of new item codes.

Low risk.

All excipients comply with USP and EP specifications.

Tubing Platinum cured Silicone tubing is used. Platinum cured Silicone tubing available

will be used.

As part of the Technology Transfer to the new manufacturing site, the tubing, already available will be used in order to decrease the number of new item codes.

Low risk.

The tubing material is the same (Platinum cured Silicone) and, therefore, incompatibility issues are not predicted.

Nevertheless, product compatibility with the tubing will be assessed during the manufacture of the PPQ batches.

Container Closure System

Vial 20 mm neck, type I glass, tubular vials

from manufacturer “a” 20 mm neck, type I glass, tubular vials

from manufacturer “b”

As part of the Technology Transfer to the new manufacturing site, container closure system components already available will be used in order to decrease the number of new item codes and to run properly in the equipment available.

Low risk.

The type of glass and the capacity of the vials are the same.

Nevertheless, the impact of this change will be assessed during the manufacture of the PPQ batches.

Stopper RTU bromobutyl stoppers, 20 mm RTS bromobutyl stoppers, 20 mm

Low risk.

The elastomer is the same and, therefore, incompatibility issues are not predicted. RTS stoppers will undergo a validated sterilization cycle.

Nevertheless, the impact of this change will be assessed during the manufacture of the PPQ batches.

Seal Dark blue flip-off caps, 20 mm Dark blue flip-off caps, 20 mm N/A No risk.

The same type of seals will be used.

85

Process Step Item Current manufacturing site New manufacturing site Rationale for the change proposed Risk evaluation

Compounding

Batch size The batch size is 100 L (compounded in

a 100 L tank). The batch size will be 200 L (to be

compounded in a 250 L tank).

The batch size was selected based on the equipment available and market demand.

Low risk.

Compounding conditions will be evaluated for the new batch size (200 L batch size compounded in a 250 L tank). The product is not sensitive to oxygen and, therefore, the headspace in the preparation tank is not expected to have any impact on the product quality.

Initial WFI amount

The initial amount of WFI added to the tank is 70 % of final Q.S. weight.

The initial amount of WFI to be added to the tank will be 90 % of final Q.S.

volume.

During evaluation of the process, some API dissolution issues were noticed and it was concluded that increasing the initial WFI amount would enhance the API dissolution.

Medium risk.

The suggested amount of initial WFI is intended to allow proper API dissolution, in order to improve the compounding process and to solve the dissolution issues noticed during evaluation of the process.

The impact of this change will be assessed during the manufacture of the PPQ batches.

Compounding temperature

15 – 25 ºC 20 – 25 ºC During evaluation of the process, it was noticed that the API solubility is compromised below 20 ºC.

Low risk.

The temperature upper limit will remain the same and, therefore, there is no risk of product degradation. Tightening the temperature range will avoid incomplete API dissolution at low temperatures.

Preparation of pH

adjustment solutions

0.5 N pH adjustment solutions are used. 1 N pH adjustment solutions will be

used.

Since a higher amount of WFI will be initially added to the tank, it is recommended to use a more

concentrated pH adjustment solution in order to leave more room for Q.S. and

to ease the pH adjustment.

Low risk.

The IPC pH range remains the same, regardless of the pH adjustment solution concentration.

Nevertheless, the impact of this change will be assessed during the manufacture of the PPQ batches.

Filtration Filters Filter cartridges are used. Filter capsules will be used.

Due to the unavailability of housings in the new manufacturing site, filter

capsules with the same filter membrane will be used.

Low risk.

The same filter membrane will be used. Sterile filtration validation studies are available and include both cartridge and capsule filters.

Risk evaluation:

No risk – No change and, therefore, there is no impact on the product quality.

Low risk – Low risk, which is not expected to have any impact on the product quality. Nevertheless, the impact of the proposed changes will be assessed during process validation.

Medium risk – Acceptable risk, which might have an impact on the product quality. Therefore, the impact of the proposed changes will be assessed during process validation.

High risk – High risk, which is expected to have an impact on the product quality. Therefore, the impact of the proposed changes will be assessed with additional studies.