PROCESS VALIDATION OF LYOPHILIZATION PROCESS A...

www.wjpps.com Vol 7, Issue 1, 2018.

365

Mishra et al. World Journal of Pharmacy and Pharmaceutical Sciences

PROCESS VALIDATION OF LYOPHILIZATION PROCESS A

REVIEW

Aditya Mishra*, Dr. T. R. Sainia and Dr. V. K. Maurya

b

*,aDepartment of Pharmacy Shri G. S. Institute of Technology and Science, Indore, Madhya

Pradesh 452003.

bGovt. College of Pharmacy, Aurangabad, Aurangabad, Maharashtra 431005.

ABSTRACT

Lyophilization mainly considered as one of best method to promote the

long-term stability of many pharmaceutical drug product.

Lyophilization, more generally known as “freeze-drying,” is a means

of dehydration process (a process that remove water molecules/

desiccation) used in the foods like meat industries, many chemicals

industries, pharmaceutical, and biotechnology industries. In each of

cases, lyophilization is used to promote the long term stability of a

decomposable product and /or making the product easier to transport

or/ and store in different words the degradative or less stable in an

aqueous medium of these systems forms a real barrier against the

clinical use of many pharmaceuticals. In the biotechnology industry

and most other pharmaceutical industries, lyophilization /freeze drying is used as a last

processing step for purified active pharmaceutical ingredients (APIs) or/ and drug

formulation to stabilize the protein and other pharmaceuticals for long-term storage. This

article reviews the state of the art of lyophilization and process validation considerations of

freeze dried product with parameter of PAT and QbD tools in each stage. This review

discusses about the most important parameters that promote the success of lyophilization of

these frangible systems, and gives an overview of freeze-drying process and formulation

strategies which is focused on the impact of formulation and process on particle stability

point of view.

KEYWORDS: Process validation, Lyophilization, QbD, Primary Drying, Secondary Drying,

Freezing, Quality, Sublimation, PAT, Freeze- Drying.

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 6.647

Volume 7, Issue 1, 365-397 Review Article ISSN 2278 – 4357

*Corresponding Author

Aditya Mishra

Department of Pharmacy

Shri G. S. Institute of

Technology and Science,

Indore, Madhya Pradesh

452003.

Article Received on

11 Nov. 2017,

Revised on 30 Nov. 2017,

Accepted on 21 Dec. 2017

DOI: 10.20959/wjpps20181-10766


366


1. Lyophilization

Lyophilization is the most general technique for formulating Parenterals products when

stability in aqueous solution is an issue. It is central to the protection of materials, which

require low moisture content (less than 1%) in order to ensure stability and require a sterile

and gentle preservation process. Lyophilization produces excellent quality products, both

foodstuff and pharmaceuticals, due to the moderate temperatures at which the process takes

place, contributing to the formation of highly porous solids that retain aroma, colour, and

flavour.[1,2]

Vacuum lyophilization takes place at very low pressures so that the operation

occurs below the triple point of water, leading to high investment and operating costs.[2,3]

Lyophilization is a technology, method, process by a product is frozen (converting all mater

to solid state) and then water removed by sublimation (primary drying) of the freezed water

molecule (solid particles) i. e. Ice. The complete process of freeze drying requires steps;

freezing of the molecule in witch water is there by nucleation and many other method; after

that second step is main drying (MD) by this sublimation of the ice molecules happens; then

secondary drying (SD) in this step desorption of the water molecule which is bounded to the

solid particle or particles, and in the last packing should be done in the vails/ containers to

prohibit reabsorption of water and/or oxygen from the atmosphere. With the help of freeze-

drying a product unstable/ less stable / decomposable/ degradative in the presence of moisture

is converted into a dried and stable formulation.[4]

Development of this technique to comply four demands on the Rinsed product: its volume

should remain in the frozen state, the structure and the biological activity of the dried solid

and the original substance should be same as far as possible, the dried product remains stable

during storage in room temperature. It is possible that the product can be stable at

temperatures up to 40 degree C during storage for up to 2 y;; and When water is added then

the lyophilized product is quickly reconstituted.[5]

See Fig. 1.


367


Fig 1: Steps in freeze drying of herbal material.

Pre-freezing

In lyophilization method and final temperature affect ability to successfully freeze dry the

material. In lyophilization freezing step mainly affected by cooling rate. Rapid cooling rate

mainly used for preserving stature to be examined in the microscopically but product is more

difficult to lyophilized. Slow cooling rate can use to bigger ice crystal but in the case of

human or plant cell larger crystal can rupture and product is less restriction channels in the

matrix to freeze dry.[6]

Product can be freeze by two ways. Product consist of primarily of

water, solvent material dissolved/ material suspended in the water or solute. Most sample are

eutectics which freeze at lower temperature than surrounding water. In pre freezing step on

cooling pocket are formed, ice contain pockets in which solute is present and have lower

freezing temperature than water. Product looks as frozen but it is not frozen completely till

solute in the suspension is completely frozen. Only when all of mixture (eutectic mixture) is

frozen then only product fitly frozen. This temperature is called the eutectic temperature. Pre

freezing of the formulation is performed below this temperature (eutectic temperature) before

freezing step is performed because small pockets of unfrozen suspension leftover in the

product amplify and degrade the structure stability of the lyophilized product. In other way,

formulation that bear glass formation during freeze drying process. The complete suspension


368


as the temperature lower the formulation becomes more viscous. At last the product freezes at

the point forming called as glass transition point when the formulation becomes a viscous

solid. This type of product is very difficult to lyophilized.[7–12]

1.1. Freezing

While in simple terms, the freezing step is first step in processing and apparently the most

complicated step in freeze drying process. A phase stated the “freeze-concentrate” when

water freezes the soluble particles in the product remain in the remaining liquid. At which

point ice formation became maximal, that make up the lattice when the freeze concentrate

solidifies between the ice crystals. At the stage of primary drying, ice is formed during

freezing is which is the crystalline and it‟s removed by sublimation. That‟s why, the vapor

pressure of the chamber is decreased below the ice vapor pressure, and the temperature of

shelf is increased to supply the heat removed by sublimation of ice.[13]

Fig 2: Phase diagram of water - Ice- Vapor system

As per Fig. 2 (phase diagram of water)[14]

, most product are frozen well below their

eutectic/glass transition point (A). Temperature is decreased to just below critical temperature

(B). No matter what type of freeze drying system is used condition must be crated to

encourage the free flow of water molecule. Therefore vacuum pump is an essential

component of a freeze drying system and is used to lower the pressure (C). the molecule have

a natural affinity to move towards the collector chamber because it‟s vapour pressure is lower


369


than that of the product. Therefore the collector temperature (D) must be significantly lower

than the product temperature.

So freezing can be define as it is a process when ice crystallization occurs from super cold

water. In simple, in freezing process first Colling of solution that will lead to “nucleation”

(nucleation is a process in which small nuclei is formed in solution or saturated solution). The

degree of supercooling is mainly responsible for the rate of ice growth, number of ice nuclei

formed, and the ice crystal‟s size.[16]

That will lead to growing of Ice crystals at a defined

rate, freeze concentration of the solution will be formed, a process that can result in

crystalline and amorphous solids, or in mixtures of amorphous & crystalline.[17,18]

The

freezing rate of a formulation is not necessarily related to its cooling rate.[18]

Because the

cooling rate is defined “as the rate at which a solution is cooled & the freezing rate is the rate

of post nucleation ice crystal growth, which is largely determined by the amount of

supercooling prior to nucleation”.[17–19]

Ice nuclei getting more time to grow when providing slow rate of freezing, the ice will grow

and form the ice crystals and solution which is present in between the crystal becomes more

concentrated. But in the case rapid freezing will leads to grow small and the remaining

solution will become so much vicious. As the viscosity increased, water molecule becomes a

part of concentrated liquid (glass) in between ice crystals and not able to diffuse.[17]

The cryoprotective effect of four carbohydrates (glucose, fructose, mannose and maltose) on

paradodecanoyl-calixarene based SLNs (solid lipid nanoparticles) has been investigated by

PCS (photon correlation spectroscopy) and these four carbohydrates have been shown to act

as good cryoprotectants, allowing reconstitution of the suspensions after the freeze-drying

process.[6,20]

If other solid/ dissolved substances are present the freezing behaviour of water

changes differently, e.g. cryoprotective agents (CPAs). They all protect quality of the product

to be lyophilized in one way or another, they can be used in alone or in combination.

Lyophilization of liposomes without special protectants, cryoprotectors, causes them to

coalesce and aggregate. The included water-soluble drug can also leak out.[6]


370


The most commonly used cryoprotectants material can be classified in Fig 3.[21]

Fig 3: commonly used cryoprotectants material.

1.1.1. Freezing method

There are several freezing method are describe[6,22]

Shelf-ramped freezing

Pre-cooled shelf method

Annealing

Quench freezing Quench

Directional freezing

Ice fog technique

Electro-freezing

Ultrasound-controlled ice nucleation

High-pressure shift freezing or depressurization technique

Vacuum-induced surface freezing

Non-aqueous co-solvents

Addition of ice nucleating agents

Others


371


1.2. Primary drying

Primary drying is also known as main drying because in this phase of lyophilisation

sublimation occurs. Sublimation occurs when a frozen solvent passes to gaseous phase

without passing through liquid phase. The crystals of ice by using a special freezing method

will grow extremely uniformly. The ice sublimes and the remaining solids show their original

structure after freezing. In the process of sublimation the ice temperature at the sublimation

front (Tice) should be done at well below the collapse temperature (Tc).[17]

The end of the

sublimation phase corresponds to the decrease in the moisture sensor signal down to a low

constant value.[23]

The vapour transportation of vapour and supply of heat to the condenser

which is shown Fig. 4 are most important parameter during primary drying. That‟s why the

operation pressure is a very mandatory tool to control Tice, if the temperature of shelf is

conserved constant and the temperature of condenser is always down to a maximum, which

depends on the design of the plant and water vapour pressure in the chamber. Sublimation is

a process when matter directly convert from solid state to vapour state without melting (liquid

Phase). Sublimation occurs at a controlled environment for a particular substances at define

range of pressures and temperatures.[24]

The phase diagram of pure water shows that

sublimation of water ice can be done when the temperature and vapor pressure are below the

triple point of water - i.e., below 0.010C and 611.73 Pa, accordingly.

Fig 4: The collecting system which acts as a cold trap to collect the vapors.

In the end of sublimation process most of the water which is present in the form of moisture

removed from formulation.[17]

In lyophilizer, vapour is formed after sublimation process in


372


lyophilization chamber goes to condenser. Condenser continuously remove it.[25]

When main

drying MD completed the most of the ice is sublimated. And the standard deviation of Tice

above the measured Tice decreases during MD. This parameter can be utilized to change

continuously from second stage to third stage that is main drying MD to secondary drying

(SD), e.g. if the average becomes 2-30C above than measured Tice the during main drying

(MD).[17]

1.3. Secondary drying

After primary drying all ice will be sublimated but moisture will be present in form of bound

to the solid particle pf formulation. The formulation seems to be dried but it‟s not because of

bound residual moisture can be present as high as 7-8%, so it is mandatory to drying at higher

temperature. This will leads to reduce the moisture. When the bound water is desorbed from

formulation then it‟s called as Isothermal Desorption. Secondary drying carried out at high

vacuum and moderate temperature (20–60°C). The dryer loses shelf control for 30 mins

during secondary drying as a result of a brief power outage. This results in the shelf

temperature being maintained at 5°C cooler than the set point of 25°C. In the freeze drying

process the third stage secondary drying is used for desorption of water which is present in

the bound form until target residual water content is achieved. At this this stage, the drying

temperature is more important determinant of the amount of moisture with drying time.[26]

1.4. Sealing Lyophilized Products

A freeze dried product should be closed within its container before removing it from the

ultra-dry atmosphere present at the end of the freeze drying process. The formulation which

has been go through this cycle most of the time it contains less than 1 % of moisture, so when

it will come contact with moisture containing environment, product will try to take moisture

as its capacity. The quality of the product will be degraded immediately. Enhanced chemical

performance, increased shelf life, and rapid reconstitution properties required by lyophilized

product after freeze drying, will be compromised. If moisture is again taken by product then

loss of product, false result, product failure and product recalls will be consequences. To use

of packages that can‟t be sealed inside the lyophilizer before to re-pressurization that is the

most common mistake by companies. For example, the manufacturing process for some

diagnostic products can require lyophilizing the product inside a large number of screw-top

tubes. Sealing of these tubes inside of a lyophilizer before terminating the batch, there is no

practical way, that‟s why the company will gather a large production staff to apply manually


373


to a room which is incompatible with freeze drying process. Recently, stable chemistry will

be endangered by the risk of unacceptable high and variable moisture levels during manual

sealing process. So exposing lyophilized material to atmospheric moisture in this way may

result in an unstable product.[27]

For the successful performance of any lyophilization process all four stages of the

lyophilization process (freezing, primary drying, secondary drying and sealing) carrying

equally importance , So it can produce a dried and stabilized product for storage at long-term.

Subsequent steps, final moisture level, or quality of overall product can largely affected by

any change in one step of any stage of lyophilization cycle. The basic principles of

lyophilization must be understand and then it should apply to lyophilization process and

individual product. To ensure proper “validation proper process qualification and continuous

process monitoring” should be performed.

For scrutinizing the process is under control or not, process validation of lyophilization

process should include the validating process variables of formulation. This process should

take consideration of critical variables a. e. Final mixing, filtration, filling, partial stoppering

of three batch after that stoppering sealing sand packing.

2. PROCESS ANALYTICAL TECHNOLOGY (PAT)

PAT is defined as „a system for designing, analyzing and controlling manufacturing through

timely measurements (in and after processing) of critical quality and performance attributes

of raw and in-process materials and processes with the goal of ensuring final product quality‟.

PAT is a unique approach for process validation. It combines techniques, procedures and

tools like quality by design (QbD) and real time release (RTR) that enable online and offline

verification of key process parameters. PAT creates a robust control strategy for the ongoing

process monitoring. PAT is thus, increasingly explored and adopted by pharmaceutical and

biotechnological set ups for enhanced process understanding and risk management. In the

PAT Table 1 shows the type of measurement for characteristics with method is used and

Table 2 explain how the PAT can be for lyophilization process with the help of stages,

physical parameter. In this process most of the control parameter is mentioned in Table 3.

PAT from an implementation perspective is visualized as a three-step process.

Design

Analysis


374


Control

Table 1: Process analysis measurement.

Type of PAT

measurements Method Characteristics

In-line No removal of the sample

Quick and quality result

obtained. on-line

Sample is diverted from the

main process, analyzed and

may be returned

at-line Sample is removed and

analyzed closed to the process. More time consuming.

off-line

Sample is removed and

analyzed away from the

process.

Difference between at-line

and off-line measurements

in lab scale processing is

tough to define.

Table 2: PAT for Freeze-Drying Process Development.

Stages Physical parameter Tools of Process analytical

technology (PAT)

Potential product

quality product

Freezing Ice nucleation

temperature

Ice fog

Nucleation-technique Controlled-ice

Reconstitution

time

Residual water

Physical stability

Cake appearance

Primary drying

Product temperature,

Sublimation rate

Drying time

Gas flow velocity

Vail heat transfer

Product resistances

coefficient

Manometric temperature

measurement (MTM)

Freeze drying

Control system

Wireless temperature monitoring

Pirani gauge

Spectroscopic-technique

residual gas analyzer (RGA)

Secondary

drying

Residual water

Product temperature

Drying time

Tuneable diode laser absorption

spectroscopy (TDLAS)

Table 3: Process Control Parameters.

S. No. Parameters Source Source

1 Product Final Mixing

Testing End Product

1.1 Description of formulation

1.2 pH after and before reconstituted

1.3 % Assay of API

2 Filtration

2.1 Sterility Test of the final formulation

3 Filling of Bulk

3.1 Filled Volume of Bulk

3.2 % Assay at Bulk

4 Lyophilization

4.1 Water Content in %

5 Sealing of Vials (Full Stoppered)


375


5.1 Leak Test of vails

6 Description

Testing In Process

7 Content of Water

8 Average Weight of Cake

9 Dosage form Uniformity

10 Constituted solution

11 Description of solution

12 Time take to Reconstitution

13 Particulate matter in the solution

14 pH of the bulk

15 Bacterial Endotoxins limit

16 Sterility

17 % Assay

18 Relative substances

3. QUALIY BY DESIGN (QbD)

Pharmaceutical Quality by Design (QbD) is a systemic, scientific, risk-based, holistic and

proactive approach to pharmaceutical development that begins with predefined objectives and

emphases product and processes understanding and process control based on sound science

and quality risk management. The relationships between formulation and manufacturing

process variables which must include excipient attributes, drug substances, and process

parameter and product characteristics are established then Source of quality variation

identified. Because of this knowledge and experience used to regulate a robust and flexible

process of manufacturing than can be adapted and produce a consistent quality product.

Process understanding is a major goal of a QbD program.[28,29]

QbD include following

element.[15]

Define target product quality profile

Design and develop product and manufacturing process

Identify critical quality attributes, process parameter, and sources of variability

Control manufacturing process to produce consistent quality over time.

The variables from the first three buckets directly impacts the process performance and

imposes boundaries on the “Design Space” while the variables from the fourth bucket not so

much influence the process but impacts the product quality attributes. The next step is to

design multivariate experiments supported with the stability studies to determine the degrees

of impact each parameter has on the CQAs. This evaluation could be based on statistical

significance in the experiments and, process parameters that significantly impact CQAs will

be categorized as Critical Process Parameters (CPP) and those that are not but are important


376


for consistency of the process performance or other business related factors are categorized as

Key Process Parameters (KPP). The parameters or material attributes that are demonstrated to

be influential and critical to the CQAs need to be further studied using DOEs involving

multivariate combinations and interactions with other parameters to define the operating

boundaries around the target within the design space. These studies can be performed using a

scale-up model that mimics and represents the commercial scale freeze dryer conditions. The

validity of the model and the operating space within the design space can be confirmed and

demonstrated with a verification experiments at full scale. In order to have the understanding

and data to support the non-conformances during commercial manufacturing, univariate

studies can be performed and proven acceptable limits can be established but these do not

constitute the design space.[30]

The most challenging part of the freeze drying process is the construction of the “Design

Space,” which is one of the key elements of QbD and requires thorough “Process

Understanding” which means the CPPs controlling the variability in the CQAs be identified

and understood during process development so that they can be measured and controlled in

real-time during manufacturing process. One way of doing this is by using Prior-knowledge

and risk based assessment to list all the parameters that have the potential to influence the

process performance and product quality attributes. They typically fall into four buckets.

Freeze drying process operating parameters (shelf temperature, chamber pressure, ramp

rates and hold-times).

Product parameters (protein concentration, excipients and their concentrations, vial

configuration, stoppers, fill volume).

Equipment (capabilities and limitations, batch load/size, scale effects).

Components preparation and Devices.

4. PROCESS VALIDATION

The basic principle of the process of validation that should be used to produce a drug that is

suitable for its designed use. USFDA‟s Guidance for Industry on “Process Validation:

General Principles and Practices” states that “Process validation is defined as the collection

and evaluation of data, from the process design stage through commercial production, which

establishes scientific evidence that a process is capable of consistently delivering quality

product”. Definition „„Process Validation is establishing documented evidence which


377


provides a high degree of assurance that a specific process will consistently produce a

product meeting its predetermined specifications and quality characteristics‟‟.[25]

Welfare of human beings and betterment of humanity is the main one aim of science and

technology. This can be achieved by many means. It may be useful to his mental functioning

human beings so that it can be obtained from the diet and nutrition. Other limitations that

address human's intellectual and emotional needs are less clear but no less important. There is

health care in different areas of much more importance because it is directly related to

maintaining and improving the quality of human life.[25]

With the focus on verification requirements, the development of a new freeze dried product is

easy to integrate into the production environment, while attempts are made in the production

along with further development studies. In designing the freeze drying process, it is advisable

to complete the process study on the limits of the process parameter limit at time stability

studies are made. From such an approach, the selection of parameters and the more robust

process results in greater safety and efficiency.[25]

4.1. Process Validation program Contents:

Process Validation Program should be include the following points...

History of the development and product details (If available, the development report

would be useful)

Manufacturing process with a manufacturing procedure and flowchart

Equipment list mandatory for process in production

Critical production stages list for product quality

Process Validation test procedures schedule

All test procedures must contains detailed description, which include:

Acceptance criteria

Test procedure

Evaluation procedure

Sampling procedure

Intermediate and finished products Specification

Labelling of the samples


378


History and origin of process validation can be explained by Table 4[25,31]

Table 4: History and origin of process validation[25],[31]

Problem identified Enactments for problem

Year Problem Year Enactments

Early 1900s plants were revealed as unclean

conditions in meat packaging 1906

“Meat Inspection Act and

the Food and Drug Act”

1937

more than 100 people died after

taking an elixir of sulphanilamide

which was formulated using a

toxic substance

1938 “Food, Drug and Cosmetics

Act”

late 1950s

Thousands of babies were born in

Europe with birth defects.

Investigations carried out revealed

in the early 1960s that these

babies were born to mothers who

had taken the drug Thalidomide

1962

“Kefauver–Harris

amendments to the Food,

Drug and Cosmetics Act”

early to

mid-1970s

Several people died after injection

of a drug formulation that turned

out to be severely non-

conforming.

1970s

“QC approach alone is not

sufficient, but a QA

approach must be applied as

well”

early to

mid-1970s

Several people died after injection

of a drug formulation that turned

out to be severely non-

conforming.

1970s

1978

“This is regarded by many

as the true start of the

application of process

validation in industry, and

indeed the FDA in the 1970s

required and enforced

validation, especially on

sterile processes.”

“The FDA required the

process to be validated, but

the term „process validation‟

was not defined.”

1987

“FDA issued its guideline

document”

1996

“FDA issued a set of

proposed rules modifying

some of the points in the

cGMP that related to

validation”

4.2. Types of process validation

Process validation can be done by four type of method.[25,31]

4.2.1. Prospective validation

This type of process validation approach is generally main choice when the new formula

should be validated before the regular pharmaceutical production begins. Process validation


379


method normally guide to transfer development function to production manufacturing

process. Production process must be divided to many steps during development of

formulation. Each product must be evaluated important parameters on the basis of experience

or theoretical considerations to determine, which can affect the finished product quality.

4.2.2. Retrospective validation

Retrospective validation is an approach of process validation which used for operating

processes, process controls and facilities, which are not formally documented. Validation of

these facilities, processes, and process controls is can be perform by using historical data

which can give the mandatory documentary evidence so that this process is doing what is

supposed to do So that‟s why retrospective validation is can be perform whenever process is

well established. But in case change control occurs like change in composition of product,

change in the operating procedure, change in process or change in part/ parts of equipment or

equipment itself then this approach is not suitable. In recent trends this type of validation

approach is not common because of prospective validation process is perform from

development stage. Nowadays this approach mainly used in validation process audit.

List of some of the mandatory elements are.

Number of lots released per annum

An analysis of trends including those for quality related complaints.

Batches processed for a defined period (atleast10 last consecutive batches)

Manufacturer / Strength / Period / Batch Size / Year

List of process corrective and preventive action

Current specifications for active pharmaceutical ingredients/ excipient/ finished products.

. Master manufacturing / packaging documents

Data for stability testing for several batches.

4.2.3. Concurrent validation

It includes a review of the original validation attempt or repeat part of it and examining

current performance data. It can also be said in the form of re-qualification, revalidation or

re-verification of a continuous process in response to a significant change in product

components. Examples of these can be.

When process is previously validated and it going to transfer to another manufacturing

site or third party as contract manufacturer.


380


Whenever product having same ratio of inactive/ active ingredient and they are validated

then for product of different strength this approach can be a choice.

4.2.4. Revalidation

Re-validation, the name itself explain that its repeatability of validation of a part of process

or/ and whole process and which should be include reviewing of existed data of performance.

Revalidation can be understand by some example like.

Major change in the manufacturing process by which quality of the formulation can

affected.

Change in the manufacturing location.

Change in the specification and / or change in the source of Active Pharmaceutical

Ingredient.

Change in Primary Packaging material.

Changed in the batch size.

Change in the batch formula.

Modification / Change in equipment used which is expected to affect the quality of

pharmaceutical product.

4.3. Regulatory requirements for process validation

Process validation for drugs (finished pharmaceuticals and components) is a legally

enforceable requirement under section 501(a) (2) (B) of the Act (21 U.S.C. 351(a) (2) (B)).

FDA regulations describing current good manufacturing practice (CGMP) for finished

pharmaceuticals are provided in 21 CFR parts 210 and 211. To fulfilment of requirement of

FDA, all record should be available of all data of lyophilization cycle. International Society

of Pharmaceutical Engineers (ISPE)‟s Good Automated Manufacturing Practice (GAMP)

requirements will apply when data recorders are used, which should add the stipulation that

any recording equipment must be verified and validated for use in pharmaceutical processes.

Recorder which having the facility of Ethernet connectivity can store historical record and

alarm and trail of audit information is to be obtained automatically in a central database

where archiving and analysis can be done if it is necessary. “The Guide to Inspections of

Lyophilization of Parenterals, published by the US Food and Drug Administration, July 1993,

contains among others the chapters „Lyophilization Cycle and Controls‟, „Cycle Validation‟

and „Lyophilizer Sterilization/ Design‟”.[25]


381


4.4. Process validation of lyophilization

After development of freeze dried products will go to next stage scale up of manufacturing

process in this time more often validation of product and process is performed. Realization of

many benefits and pressure of regulatory requirement all the activities are underway with

respect to development pathway. There may be parameter (condition) for what type

validation will be mandatory for commercial products which are already existing, because of

compliance of requirement of regulation and if any change control or change in the process

performed. It is mainly integral part of new product development. Required application of

principal should be applied in the case change control process or in the case of revalidation.

4.4.1. Stage 1- Process design

4.4.1.1. Composing validation protocol and sops

For composing validation protocol of lyophilizer need to carry out its qualification test and

decide acceptance criteria. So during selection of size shape and other prospective need to

have one sole document. Comparing different activities of the protocol into small parts makes

communication between individuals and departments more convenient. During design

qualification as per meet the applicable user‟s requirements. During the IQ, the reviewing and

verification of utility connections, piping of the refrigeration and heat transfer system,

reconnecting the vacuum system, rewiring of the control system, start-up and testing may be

organized into distinct documents for each activity. This “modular” approach becomes more

effective and efficient as the complexity of the procedures and equipment increases. The

document should provide sufficient detail to develop the validation master plan that will

describe the approach, justification and rationale for moving to Process performance

Qualification. The theoretical results of in-process product temperature, primary drying time,

and moisture content mapping and history are consistent with the experimental results,

suggesting the theoretical model should be useful in process development and "trouble-

shooting" applications.[32]

Fig. 5 shows the documents required in different stages of the

process of process design.


382


Fig 5: Process design.

4.4.1.2. Responsibilities

Responsibility of different departments[33]

Head Quality Assurance responsible for “preparation and evaluation of the validation data as

well as deviations during execution of process validation protocol.”

Head Quality Control responsible for “analysis and evaluation of the analytical results for in-

process and finished product samples as per validation sampling plan.”

Head Production responsible for “qualification and calibration of all the processing

equipment/ instrument/ utilities and maintain its efficacy during the manufacturing.”

Engineering responsible for “qualification and calibration of all the processing

equipment/instrument/utilities and maintain its efficacy during the manufacturing.”

Research & Development responsible for “providing necessary support to the verification and

validation activity.”

Establishing acceptance criteria: - The selection of acceptance criteria is dependent on the

circumstances under which validation is being undertaken and requires judicious

consideration. If new equipment is under the qualification test then perform limitation test

challenge and based on its purpose to warrant the acceptance criteria will be decided.

Sometime OQ made to common performance capabilities of equipment.[25]

Table 5 describe

the critical parameter in freeze drying process. Table 6, 7, & 8 describe technique used for

Temp measurement, % residual moisture during late primary and early secondary drying,

miscellaneous monitors respectively.


383


Table 5: Critical parameter of lyophilization process.

STEPS Critical parameters of

PROCESS PRODUCT

STEP-1

FREEZING

RAMP

Freezing temperature and time

Annealing

Morphology

Crestline

Amorphous

STEP-2

PRIMARY DRYING

RAMP

Target product temperature

Self-temperature

Primary drying end point

Chamber pressure

Glass transition

temperature.

TRANSITION PHASE

pH

Target product temperature

Chamber pressure

Phase transition

temperature

STEP-3

SECONDARY DRYING

Heating rate

Chamber pressure

Self- temperature

Residual moisture

FINAL PRODUCT Physical appearance

Residual moisture

Physical appearance a.e.

colour & clarity after

reconstitution.

Residual moisture

Table 6: Temperature measurement during the FD process.

Technique Characteristics

Temperature Remote Interrogation

System. (TEMPRIS)

Wireless temperature sensors to observe

temperature profiles[33]

Manometric temperature

measurement.(MTM)

A valid measurement of product temperature

during primary drying even at temperatures

as low as - 45°C. It measure dry-layer

resistance and vial heat transfer coefficients

and also used for measurement of motor flux

of water[34–38]

Freeze-drying microscope (FDM) based

on time-domain Optical Coherence

Tomography (OCT).

Measure Tc of product formulations in

standard pharmaceutical vials without loss of

product quality, Provides quantitative

justification for FD above Tc and provides

an upper limit to the temperature at which a

FD cycle may run without macroscopic

product collapse. It helps to reduce the time

for primary drying and increase process

efficiency for FD products with more

accuracy than light transmission or

differential scanning calorimetry; other

benefits are product microstructure

visualization[39]

Differential scanning calorimetry (DSC). The glass transition of maximally freeze

concentrated amorphous phase (Tg‟)[40]

Freeze dry microscopy Used to determine the temperature at which

lyophile collapse occurs[41]


384


Table 7: Determine % residual moisture during late primary and early secondary

drying.

Technique Characteristics

Karl Fischer technique Not suitable for small samples[42–44]

Gravimetric method. Accuracy depends upon hygroscopic nature of sample[42]

Gas chromatography. Based on the adsorption of water from the sample using organic solvents[44]

Multipoint NIR spectroscopy In-line quantification of moisture content and hence used for drying end point

determination of a residual moisture level[45]

Multipoint NIR spectroscopy. Detection of unequal sublimation rates within a freeze-dryer shelf[23,46,47]

Phenolphthalein Colour changes of phenolphthalein show a high sensitivity to different forms

of water, which makes it possible to implement a well control over the whole

freeze-drying process.[48]

Table 8: Miscellaneous Monitors. Technique Characteristics

Raman spectroscopy (in-line) and

NIR spectroscopy and X-ray

powder diffractometry (XRPD)

(at-line)

Real time monitoring of FD processes in combination with experimental designs. Both

techniques not only complement each other, but they also provide mutual confirmation

of specific conclusions[39,40,43,49,50]

Raman spectroscopy Useful technique to monitor physical changes during FD[50–52]

Capacitive manometer Using for measuring the total pressure inside the vacuum chamber[23]

Cold plasma ionization device Plasma tool, a relevant method for monitoring FD processes

The Smart Soft Sensor The coefficient of heat transfer between the shelf and the product and the resistance of

the dried cake to vapour flow, as well as Uses the product temperature, a mathematical

model of the process, and the Kalman filter algorithm to estimate the residual amount

of ice in the vial as a function of time.[53]

XRD technique Characterize the phase transitions during FD and useful in developing a mechanistic

understanding of the solid state alterations during FD of complex, multi-component,

pharmaceutical systems[54]

scanning electron microscope (SEM) Morphology of the freeze-drying HA fibres was characterized[55–57]

The transmission electron

microscopic (TEM, Hitachi H-

7500,Tokyo, Japan)

Technique was used for this study to observe whether any change has occurred on the

morphology of final optimized nanopolymersomes during lyophilization process and

prove the conservation of vesicular integrity[58]

Frequency Modulation

Spectroscopy (FMS)

Helps to demonstrate the uniformity and create a map of headspace moisture (HSM)

for vials which allow inspection and play an important part in process validation and

quality assurance.[59]

Used to test vacuum seal integrity of lyophilized protein pharmaceuticals in glass

vials.[60]

Tunable diode laser absorption

spectroscopy (TDLAS) technique

Motor flux of water[35]

The Optical Fiber Sensors (OFS) It helps to obtain three-dimensional temperature profiles with an Optical Fiber Sensors

helix configuration which enables non-invasive, automatic loading compatible

monitoring of FD process. Allow easy handling and positioning along with detection

of excipient crystallization events.[13]

Vial impedance spectroscopy

(off-line)

Useful in the concurrent product formulation development and FD cycle without any

uncertainty introduced so as to define the critical process parameters[61]

Brunauer–Emmett–Teller (BET) by

direct flow gas absorption analysis

Specific surface area (SSA) measurement of the freeze dried samples

Temperature profile and X-ray

technique

Used to detected Sublimation during lyophilization[43]

Flow meter Motor flux of inert gas[35]


385


4.4.2. Stage 2- Process Qualification

4.4.2.1. Equipment validation

Complete process validation will include the validation of all process chemicals and raw

materials used in each unit operation, validation of all supporting facilities and utilities

necessary for the manufacturing process, qualification and validation of all process

equipment, validation of each individual unit operation, and validation of the entire process

as it is intended to be operated at commercial scale. Model based tools allow optimizing the

freeze-drying of a pharmaceutical formulation in a specific freeze-dryer, thus minimizing the

duration of the process, besides maintaining product temperature below a limit value to

preserve product quality.[62]

Equipment validation (stage of equipment validation) normally

broken down into four phase as sown in the Fig.6.[25,31]

Fig 6: Stage of equipment validation.

4.4.2.2. Construction of lyophilizer

The instrument of lyophilizer or freeze dryer is consist of following essential parts[25]

Vacuum pump

Shelf tray dryer

Control and monitoring system

Tray dryer

Shelf with controlled temperature system


386


Stop ring facility for vials

Condenser or collector chamber

Controlling and monitoring system

4.4.2.3. Equipment performance test

Separate test should be used for each function. For testing of performance of equipment

should include major system like heat transfer system, condenser & vacuum system.[25]

Testing of lyophilizer Qualification can be performed.

Condenser capacity

Shelf heating rate

Shelf cooling rate

Condenser cooling

Pressure control

Rate of Sublimation

Shelf temperature control

Leak test

System evacuation rate

4.4.2.3.1. Heat transfer system

Determination of heat transfer and temperature profile during freezing step is fundamental to

predict the final structure of a lyophilized product. Heat transfer system is used to provide a

specific temperature. Cooling is required for freezing the product and heating is required for

rate of sublimation. So cooling and heating rate along with control at set point and

temperature uniformity must be tested.[25]

In heat transfer uniformity of self-temperature

transmission plays no important role. When the guardrail was absent and Styrofoam was

replaced by the steel band. So metal band can be used as a thermal shield but some heat can

be convicts by many principle like radiation and conduction from shelf of lyophilizer at that

circumstances higher sublimation rates were observed. Radiation seem to be major effect in

heat transfer from the chamber wall to formulation.[35]

The guardrail is not much responsible

for heat transfer by conduction However for higher sublimation rates for vials located at the

side and front of an array radiation heat transfer is contributes.[63]

A significant increase in

product resistance was produced by a decrease in nucleation temperature. Self-temperature

uniformity across any one self and all of selves should be in acceptable range. The ice fog

technique was refined to successfully control the ice nucleation temperature of solutions


387


within 10C.[34]

The stated capability for self-temperature uniformity by many of lyophilizer

vendor is ± 1 degree C at the study state condition. The effect of the curvature of the vial

bottom, the heat accumulation in the glass vial and the heat transfer to the sidewalls of vials

in the corner of the shelf all contributed to a significant radial influence on the heat

transfer.[64]

Fig. 7 shows the effect of the heat transfer in shelf of lyophilizer.

Fig 7: Heat Transfer in Shelf of Lyophilizer.

Vials which present at edge get experience of heat transfer by radiation. So heat transfer rate

influenced by warmer surface. This phenomenon can be avoided by using appropriate

radiation shields.[63]

No systematic variation was observed in residual moisture an vapour

composition as load decreased.[35]

That means load on shelf decreases lead to shorter the

primary drying process. Suggesting by use of the measurements emitted on various freeze

dryer that vials present in front in a manufacturing lyophilizer getting 1.8 times lesser than

vials present in front in a laboratory freeze dryer.[65]

That‟s why, the front vials in the

laboratory are very unusual in the manufacturing sector compared to the front vials. Heat

transfer can be done different methods like Heat transfer by gas conduction, Heat transfer by

radiation.

4.4.2.3.2. Condenser

The refrigeration unit parameter like shape type, size numbers affect the shelf cooling rate on

the system. Temperature of condenser is mainly depend upon on the which solvent system

can be used aqueous or organic, for example aqueous solvent system having the commonly


388


maximum allowance temperature is -50 degree Celsius, but in the case of organic solvent like

butyl alcohol must be cooled at not much colder than water, and in the case of ethanol vapour

should be condensed at well below – 115 degree Celsius. Sublimation – condensation test can

elaborate load capacity of ice and the rate of condensation. The condensation rate can be used

to development of freeze drying cycle by setting the limit to the parameter of process, and it

can be indicated by kg of ice /h;. So the limit of product batch size can be decided be ice

capacity test.[25]

4.4.2.3.3. Freeze dry rates

Freeze dry rates mainly depend on three factor

Surface area and the thickness of the sample

The condenser temperature and vacuum obtained

The eutectic point and solute concentration of the sample.

It is important to remember these three factors when trying to obtain efficient utilization of

freeze dry system. Surface area of sample is directly proportional to the rate of freeze drying.

And as rate of freeze dry decreasing vapour pressure also decreasing. Vapour pressure

depend upon both eutectic temperature and solute concentration of the sample.

4.4.2.3.4. Vacuum

Vacuum should be enforced during the freeze drying process to remove the solvent at a

correct time. Two-stage rotary vacuum pump is used to achieve desired vacuum range which

is generally such low vacuum 50 to 100µ bar. If chamber is larger than multiple pump may

be a choice. For large chambers, multiple pumps may be used. So vacuum is to very

necessary to observed and monitor.[25]

4.4.2.4. Process testing

Process testing uses a module product to test different functions in the preceding stages of

OQ studies. In such a study, the integrity control capabilities and the capabilities of each

component of the system are challenged to implement the actual processing parameters for a

completely lyophilization cycle. So it is done after operational qualification in equipment

validation. In this studies we can locate area of monitoring or sampling. And perform the test

like product uniformity testing.[25]


389


4.4.2.5. Product qualification

Applying these validation steps to freeze drying processes and products, appropriate

recognition in the importance of development activities and growth is evident. Product

qualification can become a tool to identify the source to ensure the process is which are using

good enough or not.

4.4.2.5.1. Preformulation study

Product qualification as part of Preformulation activities, investigations, including physical

and chemical properties, optimum pH, purity, stability, solubility and density studies.[66,67]

Beta-lactam antibiotics can be solidify to a crystalline or amorphous morphology.[25]

Each

different form displays different physical properties, such as solubility and stability. When

substance undergoes phase transition then pH can be an effective factor. By choosing of some

excipients can also change the morphology of the many active drug substance.[68,69]

Development studies become critical parts of validation plan by summarize within a separate

report on development studies, drug substance characteristics, prepared product, and physical

educational aspects characteristics.[25]

4.4.2.5.2. Drug substances

The physicochemical character of the excipients and the physicochemical character of the

active ingredient govern design of product development. For example, if drugs tend to create

an amorphous or crystalline phase, then character freezing method and materials should be

evaluated during development. On the basis of theoretical point of view, when material

solidified during freezing then with compare to amorphous form a crystalline form is more

thermodynamically stable.[25,70]

4.4.2.5.3. Excipients

Freeze drying is a generally used method for product development of drug particle which are

not stable in the presence of moisture and/or unstable in high temperature. Freeze drying of

active pharmaceutical ingredient only, yet having un-doubtful product development

challenges, which can be overcome by using of many excipients (e.g. collapse temperature

modifiers, buffering agents, preservatives, wetting agent, cosolvents, tonicifying agent and

bulking agents) in the final formula. For covenants selection of excipients in the formulation

for freeze drying A needful access should be executed, because of that the formulation should

maintain an optimal functionality a. e. simple and easier processing.


390


4.4.2.5.4. Finished Product Formulation

As they are intended for parenteral administration, excipients used to formulate the freeze

dried cake must have regulatory acceptance by all means. For lyophilization of small

molecule should take account to selection criteria a, e. the list of approved excipients with

their maximum limit for finished product formulation.[25]

4.4.2.5.5. Determining Thermal Characteristics

Determination of this critical temperature is very necessary parameter for developing an

optimized freeze drying cycle. While performing primary drying of formulation, drying

temperature should below the critical temperature, which otherwise give problems i. e.

„collapse‟ or „meltback‟ phenomenon in case of amorphous substance or crystalline

respectively. Before doing experiment on lyophilization thermal parameter/ critical

temperature like Tg & Tc should be known. Eutectic temperature can be explained if in the

formulation the solute separates out in crystalline form. Besides, if it is separate out in an

amorphous form then temperature is referred to as the glass transition temperature (Tg ‟).[18]

To achieve the shelf temperature important to totally solidify the product during first step

freezing, the temperature which is required it‟s mandatory to establish complete solidification

of water and solute is scrutinized with the help of thermal analysis early in formulation

development. Apart from that optimal processing parameter should be defined in case

crystallization of product occurs at freezing.[25]

4.4.2.5.6. Finished Product Attributes

Lyophilization technique is one of the outstanding methods used for drying and producing

end products of highest quality as scrutinizing too many other drying methods. As well as the

moisture content of products is become low, the processing temperature is decreased and

most of the degradation & microbiological reactions are also ended. So that‟s why, both

preservation and value food are produced by using this lyophilization technology. If

lyophilization method the retain the physiochemical parameter of the starting formulation

solution and, rather, detention of the structure performed during first step “freezing” then the

results will be successful and effective. And assay of the constituted solution will assures the

preservation of the desired activity in the starting material which is present in it. Assay of

multiple samples of dried material is used to demonstrate content.[25]

To decide finished

product attributes should take account.

Physical Appearances


391


Residual Moisture

Reconstitution

Assay

5. CONCLUSION

Development of a successful lyophilized product can be a time- and energy consuming

process. In general, high concentration formulations are usually more resistant to both

freezing and lyophilization. Given the complexity of lyophilization process and formulation

design, attainment of a high concentration lyophilized formulation with a fast reconstitution

time requires optimization of individual process parameters and proper understanding of the

different freezing and drying stresses. This review provided an insight into the different

stresses, their impact and approaches to mitigate them for achieving the highest drug quality

at the least cost.

6. ACKNOWLEDGMENTS

This review was partially supported by ICPA HEALTH PRODUCTS LTD., GIDC

ANKLESHWAR GUJRAT. I am thankful to Mangesh Kumar Padme and my colleagues who

provided expertise that greatly assisted the research, although they may not agree with all of

the interpretations provided in this paper.

7. REFERENCES

1. Kudra T, Mujumdar AS. Advanced Drying Technologies. 2nd ed. CRC Press; 2009.

2. Branton D, Jacobson L. Freeze-drying of plant material. Exp. Cell Res. Elsevier; 1961;

22: 559–68.

3. Sagar VR, Suresh Kumar P. Recent advances in drying and dehydration of fruits and

vegetables: a review. J. Food Sci. Technol, 2010; 47: 15–26.

4. Adams G. The Principles of Freeze-Drying. In: Day JG, Stacey GN, editors. Methods

Mol. Biol. Cryopreserv. Free. Protoc. 2nd ed. Totowa, New Jersey: Humana Press Inc,

2007; 15–38.

5. Oetjen G-W, Haseley P. Freeze-Drying. 2nd ed. Weinheim: Wiley-VCH Verlag GmbH &

Co. KGaA, 2003.

6. Hottot A, Vessot S, Andrieu J. Freeze drying of pharmaceuticals in vials: Influence of

freezing protocol and sample configuration on ice morphology and freeze-dried cake

texture. Chem. Eng. Process. Process Intensif, 2007; 46: 666–74.


392


7. Leahy T, Marti JI, Mendoza N, Pérez-Pé R, Muiño-Blanco T, Cebrián-Pérez JA, et al.

High pre-freezing dilution improves post-thaw function of ram spermatozoa. Anim.

Reprod. Sci, 2010; 119: 137–46.

8. Utrera M, Armenteros M, Ventanas S, Solano F, Estévez M. Pre-freezing raw hams

affects quality traits in cooked hams: Potential influence of protein oxidation. Meat Sci,

2012; 92: 596–603.

9. López-Urueña E, Alvarez M, Gomes-Alves S, Martínez-Rodríguez C, Borragan S, Anel-

López L, et al. Tolerance of brown bear spermatozoa to conditions of pre-freezing

cooling rate and equilibration time. Theriogenology, 2014; 81: 1229–38.

10. Ruiz L, Echegaray A, Lafuente A. Seminal freezing in pure breed andalusian horse:

Difference in individual stallions and correlation between pre and post-freezing sperm

parameters. Cryo-Letters, 2011; 32: 473–6.

11. Río Segade S, Torchio F, Giacosa S, Ricauda Aimonino D, Gay P, Lambri M, et al.

Impact of several pre-treatments on the extraction of phenolic compounds in winegrape

varieties with different anthocyanin profiles and skin mechanical properties. J. Agric.

Food Chem. American Chemical Society, 2014; 62: 8437–51.

12. Silva ALP, Enggrob K, Slotsbo S, Amorim MJB, Holmstrup M. Importance of freeze-

thaw events in low temperature ecotoxicology of cold tolerant enchytraeids. Environ. Sci.

Technol. American Chemical Society, 2014; 48: 9790–6.

13. Christina J, Wiggenhorn M, Resch M, Friess W. Implementation and evaluation of an

optical fiber system as novel process monitoring tool during lyophilization. Eur. J. Pharm.

Biopharm, 2013; 83: 449–59.

14. Caupin F. Liquid-vapor interface, cavitation, and the phase diagram of water. Phys. Rev.

E. Stat. Nonlin. Soft Matter Phys, 2005; 71: 51605.

15. Mockus L, LeBlond D, Basu PK, Shah RB, Khan M a. A QbD case study: Bayesian

prediction of lyophilization cycle parameters. AAPS Pharm Sci Tech, 2011; 12: 442–8.

16. Searles JA, Carpenter JF, Randolph TW. The ice nucleation temperature determines the

primary drying rate of lyophilization for samples frozen on a temperature-controlled

shelf. J. Pharm. Sci, 2001; 90: 860–71.

17. Oetjen G-W. Freeze-Drying. Encycl. Sep. Sci. Elsevier Science, 2000; 1023–34.

18. Liu J. Physical characterization of pharmaceutical formulations in frozen and freeze-dried

solid states: techniques and applications in freeze-drying development. Pharm. Dev.

Technol, 2006; 11: 3–28.

19. Bhatnagar BS, Bogner RH, Pikal MJ. Protein stability during freezing: separation of


393


stresses and mechanisms of protein stabilization. Pharm. Dev. Technol, 2007; 12: 505–23.

20. Shahgaldian P. A study of the freeze-drying conditions of calixarene based solid lipid

nanoparticles. Eur. J. Pharm. Biopharm, 2003; 55: 181–4.

21. Abdelwahed W, Degobert G, Stainmesse S, Fessi H. Freeze-drying of nanoparticles:

formulation, process and storage considerations. Adv. Drug Deliv. Rev. [Internet], 2006;

58: 1688–713. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17118485:

10.1016/j.addr.2006.09.017.

22. Searles JA, Carpenter JF, Randolph TW. Annealing to optimize the primary drying rate,

reduce freezing-induced drying rate heterogeneity, and determine T′gpharmaceutical

lyophilization. J. Pharm. Sci, 2001; 90: 872–87.

23. Genin N, Rene F, Corrieu G. A method for on-line determination of residual water

content and sublimation end-point during freeze-drying. Chem. Eng. Process. Process

Intensif, 1996; 35: 255–63.

24. Williams NA, Polli GP. The Lyophilization of Pharmaceuticals: A Literature Review. J.

Pharm. Sci. Technol, 1984; 38: 48–60.

25. Robert A. Nash AHW. Pharmaceutical Process Validation. 3rd ed. Robert A. Nash AHW,

editor. New York: Marcel Dekker, 2003.

26. Pikal M, Shah S, Roy M, Putman R. The secondary drying stage of freeze drying: drying

kinetics as a function of temperature and chamber pressure☆. Int. J. Pharm, 1990; 60:

203–7.

27. Crist B. Time-dependence of pressure in lyophilization vials. PDA J. Pharm. Sci.

Technol, 1994; 48: 189–96.

28. Yu LX. Pharmaceutical Quality by Design: Product and Process Development,

Understanding, and Control. Pharm. Res, 2008; 25: 781–91.

29. Patel SM, Pikal MJ. Lyophilization Process Design Space. J. Pharm. Sci, 2013; 102:

3883–7.

30. Tang X (Charlie), Pikal MJ. Design of Freeze-Drying Processes for Pharmaceuticals:

Practical Advice. Pharm. Res, 2004; 21: 191–200.

31. Agalloco J, Simko RJ, Adamson JR. Validation of Pharmaceutical Processess. 3rd ed.

Agalloco J, Carleton FJ, editors. Valid. Pharm. Process. USA, 2008.

32. Pikal MJ, Mascarenhas WJ, Akay HU, Cardon S, Bhugra C, Jameel F, et al. The

Nonsteady State Modeling of Freeze Drying: In-Process Product Temperature and

Moisture Content Mapping and Pharmaceutical Product Quality Applications. Pharm.


394


Dev. Technol, 2005; 10: 17–32.

33. Schneid S, Gieseler H. Evaluation of a New Wireless Temperature Remote Interrogation

System (TEMPRIS) to Measure Product Temperature During Freeze Drying. AAPS

PharmSciTech, 2008; 9: 729–39.

34. Rambhatla S, Ramot R, Bhugra C, Pikal MJ. Heat and mass transfer scale-up issues

during freeze drying: II. Control and characterization of the degree of supercooling.

AAPS PharmSciTech, 2004; 5: e58.

35. Patel SM, Jameel F, Pikal MJ. The Effect of Dryer Load on Freeze Drying Process

Design. J. Pharm. Sci, 2010; 99: 4363–79.

36. Tang X, Nail SL, Pikal MJ. Evaluation of manometric temperature measurement, a

process analytical technology tool for freeze-drying: Part I, product temperature

measurement. AAPS PharmSciTech, 2006; 7: E95–103.

37. Tang XC, Nail SL, Pikal MJ. Evaluation of manometric temperature measurement, a

process analytical technology tool for freeze-drying: Part II measurement of dry-layer

resistance. AAPS PharmSciTech, 2006; 7: E77–84.

38. Tang XC, Nail SL, Pikal MJ. Evaluation of manometric temperature measurement

(MTM), a process analytical technology tool in freeze drying, part III: Heat and mass

transfer measurement. AAPS PharmSciTech, 2006; 7: E105–11.

39. Greco K, Mujat M, Galbally-Kinney KL, Hammer DX, Ferguson RD, Iftimia N, et al.

Accurate Prediction of Collapse Temperature using Optical Coherence Tomography-

Based Freeze-Drying Microscopy. J. Pharm. Sci, 2013; 102: 1773–85.

40. Elgindy N, Elkhodairy K, Molokhia A, Elzoghby A. Lyophilization monophase solution

technique for preparation of amorphous flutamide dispersions. Drug Dev. Ind. Pharm,

2011; 37: 754–64.

41. Kremer DM, Pikal MJ, Petre WJ, Shalaev EY, Gatlin LA, Kramer T. A procedure to

optimize scale-up for the primary drying phase of lyophilization. J. Pharm. Sci, 2009; 98:

307–18.

42. Patel SM, Doen T, Pikal MJ. Determination of end point of primary drying in freeze-

drying process control. AAPS PharmSciTech, 2010; 11: 73–84.

43. Schelenz G, Engel J, Rupprecht H. Sublimation during lyophilization detected by

temperature profile and X-ray technique. Int. J. Pharm, 1995; 113: 133–40.

44. Robinson LC. A gas chromatographic method of measuring residual water in freeze-dried

smallpox vaccine. Bull. World Health Organ, 1972; 47: 7–11.

45. Kauppinen A, Toiviainen M, Korhonen O, Aaltonen J, Järvinen K, Paaso J, et al. In-Line


395


Multipoint Near-Infrared Spectroscopy for Moisture Content Quantification during

Freeze-Drying. Anal. Chem, 2013; 85: 2377–84.

46. Kauppinen A, Toiviainen M, Lehtonen M, Järvinen K, Paaso J, Juuti M, et al. Validation

of a multipoint near-infrared spectroscopy method for in-line moisture content analysis

during freeze-drying. J. Pharm. Biomed. Anal, 2014; 95: 229–37.

47. De Temmerman J, Saeys W, Nicolaï B, Ramon H. Near infrared reflectance spectroscopy

as a tool for the in-line determination of the moisture concentration in extruded semolina

pasta. Biosyst. Eng, 2007; 97: 313–21.

48. Liu L, Wang Y, Fan D, Mi Y. Using phenolphthalein as a promising indicator to monitor

the vacuum freeze-drying process. Mater. Lett, 2015; 139: 245–8.

49. De Beer TRM, Vercruysse P, Burggraeve A, Quinten T, Ouyang J, Zhang X, et al. In-line

and real-time process monitoring of a freeze drying process using Raman and NIR

spectroscopy as complementary process analytical technology (PAT) tools. J. Pharm. Sci,

2009; 98: 3430–46.

50. Hédoux A, Paccou L, Achir S, Guinet Y. In Situ Monitoring of Proteins during

Lyophilization using Micro-Raman Spectroscopy: A Description of Structural Changes

induced by Dehydration. J. Pharm. Sci, 2012; 101: 2316–26.

51. Romero-Torres S, Wikström H, Grant ER, Taylor LS. Monitoring of mannitol phase

behavior during freeze-drying using non-invasive Raman spectroscopy. PDA J. Pharm.

Sci. Technol, 2007; 61: 131–45.

52. De Beer TRM, Allesø M, Goethals F, Coppens A, Vander Heyden Y, Lopez De Diego H,

et al. Implementation of a Process Analytical Technology System in a Freeze-Drying

Process Using Raman Spectroscopy for In-Line Process Monitoring. Anal. Chem, 2007;

79: 7992–8003.

53. Bosca S, Barresi AA, Fissore D. Use of a soft sensor for the fast estimation of dried cake

resistance during a freeze-drying cycle. Int. J. Pharm, 2013; 451: 23–33.

54. Cavatur RK, Suryanarayanan R. Characterization of Phase Transitions During Freeze-

Drying by In Situ X-ray Powder Diffractometry. Pharm. Dev. Technol, 1998; 3: 579–86.

55. Chen J, Peng C, Nie J, Kennedy JF, Ma G. Lyophilization as a novel approach for

preparation of water resistant HA fiber membranes by crosslinked with EDC. Carbohydr.

Polym. Elsevier Ltd, 2014; 102: 8–11.

56. Karcz J, Bernas T, Nowak A, Talik E, Woznica A. Application of Lyophilization to

Prepare the Nitrifying Bacterial Biofilm for Imaging with Scanning Electron Microscopy.

Scanning, 2012; 34: 26–36.


396


57. De Temmerman M-L, Rejman J, Grooten J, De Beer T, Vervaet C, Demeester J, et al.

Lyophilization of Protein-Loaded Polyelectrolyte Microcapsules. Pharm. Res, 2011; 28:

1765–73.

58. Ayen WY, Kumar N. A systematic study on lyophilization process of polymersomes for

long-term storage using doxorubicin-loaded (PEG)3–PLA nanopolymersomes. Eur. J.

Pharm. Sci. Elsevier B.V., 2012; 46: 405–14.

59. Cook IA, Ward KR. Headspace Moisture Mapping and the Information That Can Be

Gained about Freeze-Dried Materials and Processes. PDA J. Pharm. Sci. Technol, 2011;

65: 457–67.

60. Lin TP, Hsu CC, Kabakoff BD, Patapoff TW. Application of frequency-modulated

spectroscopy in vacuum seal integrity testing of lyophilized biological products. PDA J.

Pharm. Sci. Technol, 2004; 58: 106–15.

61. Arshad MS, Smith G, Polygalov E, Ermolina I. Through-vial impedance spectroscopy of

critical events during the freezing stage of the lyophilization cycle: The example of the

impact of sucrose on the crystallization of mannitol. Eur. J. Pharm. Biopharm. Elsevier

B.V., 2014; 87: 598–605.

62. Pisano R, Fissore D, Barresi AA. In-Line and Off-Line Optimization of Freeze-Drying

Cycles for Pharmaceutical Products. Dry. Technol. Palma. Balearic Island, Spain, 2013;

31: 905–19.

63. Rambhatla S, Pikal MJ. Heat and mass transfer scale-up issues during freeze-drying, I:

atypical radiation and the edge vial effect. AAPS PharmSciTech, 2003; 4: E14.

64. Brülls M, Rasmuson A. Heat transfer in vial lyophilization. Int. J. Pharm, 2002; 246:

1–16.

65. Rambhatla S, Tchessalov S, Pikal MJ. Heat and mass transfer scale-up issues during

freeze-drying, III: control and characterization of dryer differences via operational

qualification tests. AAPS PharmSciTech, 2006; 7: E39.

66. Expósito Raya N, Mestre Luaces M, Silva Rodriguez R, Nazábal Gálvez C, Peña Rivero

M, Martínez de la Puente N, et al. Preformulation study of the vaccine candidate P64k

against Neisseria meningitidis. Biotechnol. Appl. Biochem, 1999; 29( Pt 2): 113–7.

67. Devi S, Williams DR. Density dependent mechanical properties and structures of a freeze

dried biopharmaceutical excipient--sucrose. Eur. J. Pharm. Biopharm. Elsevier B.V.,

2014; 88: 492–501.

68. Randolph TW. Phase separation of excipients during lyophilization: effects on protein

stability. J. Pharm. Sci, 1997; 86: 1198–203.


397


69. Kolhe P, Amend E, K. Singh S. Impact of freezing on pH of buffered solutions and

consequences for monoclonal antibody aggregation. Biotechnol. Prog, 2009; 26: 727–33.

70. Oberholtzer ER, Brenner GS. Cefoxitin sodium: solution and solid-state chemical

stability studies. J. Pharm. Sci, 1979; 68: 863–6.

PROCESS VALIDATION OF LYOPHILIZATION PROCESS A...

Documents

Transcript of PROCESS VALIDATION OF LYOPHILIZATION PROCESS A...