tech trans lyophilized inj

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Lallu R.M. et al. World Journal of Pharmacy and Pharmaceutical Sciences

TECHNOLOGY TRANSFER PROCESS OF LYOPHILIZED

INJECTION

Lallu Rachel Mathai*, Siva.P

Department of Pharmaceutics, Grace College of pharmacy, Palakkad, Kerala 678004.

ABSTRACT

This study is focussed on the technology transfer process of the

parenteral product which is made into a compact cake by the process of

lyophilization.The drug which is unstable in liquid form or has poor

oral bioavailability is lyophilized by optimising the lyo-cycle ,based on

the trials taken.Thus the optimised process is subjected to scale up

,transferred to commercial scale production.The product is evaluated

for its characteristics which should be in line to the specifications of

the innovator product. Development of stable injectable dosage form

was possible as the moisture content of the formulation is greatly

reduced thus enhancing the stability of the product, ease of handling,

rapid dissolution because of porous nature of the cake and easier

transport of the material during shipping.

Key words:Technology transfer,lyophilisation,lyo-cycle,eutectic temperature.

INTRODUCTION

In pharmaceutical industry “technology transfer” refers to the processes that are needed for

successful progress of drug discovery to product development to full scale

Commercialization. Technology transfer is a key business process, supporting the

introduction of newly developed products and also the movement of products between the

sites.

Technology transfer can be divided in to 2 types

1)Tech transfer: In tech transfer, the product is developed in lab-scale, subjected to scale-up,

exhibit batch to full scale commercialization.

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Article Received on 08 February 2013, Revised on 07 March 2013, Accepted on 29 March 2013

*Correspondence for

Author:

* Lallu Rachel Mathai,

Department of Pharmaceutics,

Grace College of pharmacy,

Palakkad, Kerala, India.

[email protected]

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2)Site transfer: In site transfer the product from the outside customer are subjected to lab-

scale feasibility trials and then to commercial scale depending on customer need.

Process of technology transfer:

Laboratory trials of appropriate size will be made and samples will be analyzed for all

critical parameters.

Analytical method validations of assay, dissolution and related substances will be carried

out along with degradation studies.

Pilot batch will be made after achieving the satisfactory results during the manufacturing

of trial batches and samples are analyzed.

Samples, test reports and batch documents will be sent to corporate technical team for

their review and comments. Necessary reference/working standard materials including

impurities will be procured.

Analysis of raw material, in process samples and the finished product will be carried out

against the reference / working standards.

QA in co-ordination with production will prepare the batch record. QC will prepare the

analytical specification for raw material (if any new raw material is involved in the product),

packing specification, in-process specification and finished product specification.

If customer requires reviewing the documents, the batch records and process validation

protocols will be forwarded to them for their approval through International business

department. Process validation of first three commercial batches will be carried out at

manufacturing site identified for commercial production and will be kept on stability studies

as per ICH guidelines.

Technology transfer department will be responsible completely till the technology is

transferred satisfactorily to respective sites.

Transfer of technology will be completed only after satisfactory completion of first three

consecutive commercial batches at the manufacturing site.

After completion of first three batches of the product, documents will be forwarded to the

customer for their review if required by customer.

Batch Manufacturing Record.

Batch Packing Record.

Validation Protocol & Reports.

Certificate of analysis of batches & Raw materials.

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Specimen sample of the product will also be sent to the customer.

For a successful scale-up of freeze drying process, it is important to develop a systematic

strategy to correlate the cycle parameters obtained from small-scale operation to final results

obtained from full-scale production operations under various operational conditions, such as

shelf temperature , chamber pressure, type of vial, and solution depth. Appropriate scale-up

of a freeze drying process in a cost effective and efficient manner involves smart use of

experimental tools to monitor the drying process of product. It is hypothysed that cycles

developed and /or used in the laboratory drier will correlate to cycles used in the production

dryer. Predicting production freeze dry cycle parameters from laboratory experiments has

obvious advantage. Small initial batches conducted in the laboratory dryer will establish an

optimum cycle for a product that may be modestly adjusted to transfer the product to a

production dryer.

Lyophilization or freeze drying is a process in which water is removed from a 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 consists of three separate, unique,

and interdependent processes; freezing, primary drying (sublimation), and secondary drying

(desorption).

Methodology

The lyophilization process generally includes the following steps:

1. Dissolving the drug and excipients in a suitable solvent, generally water for injection

(WFI).

2. Sterilizing the bulk solution by passing it through a 0.22 micron bacteria-retentive filter.

3. Filling into individual sterile containers and partially stoppering the containers under

aseptic conditions.

4. Transporting the partially stoppered containers to the lyophilizer and loading into the

chamber under aseptic conditions.

5. Freezing the solution by placing the partially stoppered containers on cooled shelves in a

freeze-drying chamber or pre-freezing in another chamber.

6. Applying a vacuum to the chamber and heating the shelves in order to evaporate the

water from the frozen state.

7. Complete stoppering of the vials usually by hydraulic or screw rod stoppering

mechanisms installed in the lyophilizers.

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DESIRED CHARACTERISTICS OF FREEZE-DRIED PRODUCTS:

Intact cake

Sufficient strength

Uniform colour

Elegant appearance

Sufficiently dry

Sufficiently porous

Sterile

Free of pyrogens

Free of particulates

Chemically stable

THE LYOPHILIZATION PROCESS

Stages of free drying:

The Lyophilization process consists of three separate, unique and inter-dependent processes

namely

Freezing

Primary drying (sublimation),

Secondary drying (desorption of unfrozen water).

Figure 1: process of Lyophilization

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1.Freezing (Solidification)

Freezing is generally the first step in a freeze-drying process, in which nearly 90% of the

water is converted to ice crystals while all solutes in the formulation are solidified into a

matrix either in amorphous or crystalline state, or in a mixture.

In general, freezing is defined as the process of ice crystallization from super-cooled

water12. The freezing process first involves the cooling of the solution until ice nucleation

occurs. Ice crystals begin to grow at a certain rate, resulting in freeze concentration of the

solution, a process that can result in either crystalline or amorphous solids or in

mixtures13.

Rapid cooling results in small ice crystals, useful in preserving structures to be examined

microscopically, but resulting in a product that is more difficult to freeze dry. Slower

cooling results in large ice crystals and less restrictive channel in the matrix during the

drying process.

In the freezing step, the product is cooled below the glass transition temperature or the

eutectic point of the solution in order to stabilize the product and form ice.

2.Primary Drying (Ice sublimation)

In this step heat is supplied to the product in the presence of vaccum. In this phase the

chamber pressure is reduced up to 0.01 to 0.1mbar by introducing vacuum in to the product

chamber. Heat is applied to the product to cause the frozen mobile water to sublime15, 16, 17.

Throughout this stage, the product is maintained in the solid state below the collapse

temperature of the product in order to dry the product with retention of the structure

established in the freezing step. 18 It is an important that the product temperature does not go

higher than the Tg, as this can cause the product to collapse19 as in the vial on the right in

Figure below.

Figure 2: Normal Product Compared (left) to Collapsed Product (right)

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Collapse is a change in the morphology, solubility and chemical integrity when molecules

change back into the liquid state .This will cause degradation of the product and change the

physical characteristics of the dried material, make it harder to reconstitute and visually

unappealing. Primary drying occurs at a low temperature and pressure.

Collapse occurs when the pressure and temperature is increased above triple point as

indicated on the phase diagram below.

In freeze drying, the temperature of the product is increased at constant pressure, so one

would be moving from the left to the right on the graph of Figure 3 below.

In general, a safety margin should be kept during primary drying, that is, the product

temperature (Tp) should be 2–5ºC below Tc or Te. At the end of primary drying stage, the

sublimation rate will be significantly reduced, indicating that there is not much frozen water

left in the product. The product cools after sublimation of water, and remains colder than the

shelf temperature16, 19. When all of the ice has sublimed, the product temperature will

approach the shelf temperature and this signals the beginning of secondary drying19, 20.

Determination of Endpoint of Primary Drying

Once the shelf temperature reaches the set point, the primary drying continues under the

controlled temperature and chamber pressure conditions until the end of the ice sublimation.

The duration of primary drying is determined by the ice sublimation rate, the characteristics

of formulation solution and the fill volume, and thus, can be roughly estimated theoretically

by calculations based upon the mass and heat transfer equations. However, in practice, the

duration of primary drying or the end-point of ice sublimation is normally determined by

monitoring the drying progression

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Routinely, product temperatures are measured by thermocouples, the chamber pressure is

measured either by a capacitance manometer gauge or/and a thermal conductivity (Pirani)

gauge, and condenser temperature is measured by a resistive temperature detector (RTD)

sensor. At the end of primary drying, that is, the completion of the ice sublimation in a given

vial, the product temperature as measured by thermocouple shows a steep increase as it

approaches the shelf temperature.

Secondary drying

After primary freeze-drying is complete, and all ice has sublimed, bound moisture is still

present in the product. The product appears dry, but the residual moisture content may be as

high as 7 -8%, continued drying is necessary at warmer temperature to reduce the residual

moisture content to optimum values. This process is called ‘Isothermal Desorption’ as the

bound water is desorbed from the product. This desorption is used to remove water of

crystallization, randomly dispersed water molecules in a glassy material, intracellular water,

and absorbed water15,16,21 . The shelf temperature can be raised to 15-300c, for allowing the

water molecules to desorbs under vacuum. The shelf temperature should not be raised above

the product temperature; otherwise degradation of the product occurs22.The product should

not be over dried, and should not have final moisture content below 1.5 weight% in order to

preserve the cake structure. It is also important to know how much heat the product can

withstand without degrading and the shelf temperature should not be raised above this

temperature. In Figure below, secondary drying, along with freezing and primary drying, is

shown in a typical graph of product, condenser and shelf temperatures versus time. The

product temperature closely follows slightly below the shelf temperature as the water is being

desorbed. The condenser remains at a low temperature throughout the entire process

Figure 4: Temperature versus Time for Freezing, Primary Drying and Secondary

Drying

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Excipients used in lyophilized formulation

Excipients for lyophilization usually fit one of the following categories: bulking agents,

stabilizers, buffering agents, tonicity modifiers, surface-active agents23 or collapse

temperature modifiers.

A formulation may consist of one or more excipients that perform one or more functions.

Some freeze-dried formulations contain API only (e.g., cephalosporin’s, vancomycin,

antibodies) possibly because of the relatively high content of the active ingredient (typically

10 mg/ml or more) .24

Bulking agents

Bulking agents are used to provide product elegance (i.e., satisfactory appearance) as well as

sufficient cake mechanical strength to avoid product blow-out. When a very dilute solution is

lyophilized, the flow of water vapour during primary drying may generate sufficient force on

the cake to break it and carry some of it out of the vial. Bulking agents simply function as

fillers to increase the density of the product cake. 25

Amorphous excipients can serve as bulking agents, but due to relatively low collapse

temperatures most of them require long processing times, and are not favoured. Crystalline

bulking agents produce an elegant cake structure with good mechanical properties. Mannitol

and glycine are preferred since they are crystallizing compounds. Mannitol is by far the most

commonly used bulking agent. A formulation based on mannitol is usually elegant,

reconstitutes quickly, and is generally easy to freeze-dry without risk of product damages25,

except for the potential of vial breakage26, which can be minimized by small fill depths, slow

freezing, avoiding freezing temperatures less than about -25°C until crystallization is

complete25

Buffers

Buffers are required in pharmaceutical formulations to stabilize pH. A good approach is to

use low concentrations of a buffer that undergoes minimal pH change during freezing such as

citrate and histidine buffers27.

Stabilizers

The most important group of stabilizers used in freeze-drying is classified in cryo- and

lyoprotectants. They protect the API from damage during freezing (cryoprotection) and/or

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dehydration (lyoprotection) induced denaturation28.

Tonicity adjusters: -Tonicity modifiers (e.g., NaCl or glycerol) are occasionally formulated

in products for human use to make the reconstituted product isotonic (e.g., for subcutaneous

or intramuscular injections) 29.Excipients such as mannitol, sucrose, glycine, glycerol, and

sodium chloride are good tonicity adjuster

LYOPHILIZATION CYCLE AND CONTROLS

Typically, the product is frozen at a temperature well below the eutectic point.The scale-up

and change of lyophilization cycles, including the freezing procedures, have presented some

problems. Studies have shown the rate and manner of freezing may affect the quality of the

lyophilized product. For example, slow freezing leads to the formation of larger ice crystals.

This results in relatively large voids, which aid in the escape of water vapor during

sublimation. On the other hand, slow freezing can increase concentration shifts of

components. Also, the rate and manner of freezing has been shown to have an affect on the

physical form (polymorph) of the drug substance. It is desirable after freezing and during

primary drying to hold the drying temperature (in the product) at least 4-5o below the eutectic

point. Obviously, the manufacturer should know the eutectic point and have the necessary

instrumentation to assure the uniformity of product temperatures. The lyophilizer should also

have the necessary instrumentation to control and record the key process parameters. These

include: shelf temperature, product temperature, condenser temperature, chamber pressure

and condenser pressure. The manufacturing directions should provide for time, temperature

and pressure limits necessary for a lyophilization cycle for a product. The monitoring of

product temperature is particularly important for those cycles for which there are atypical

operating procedures, such as power failures or equipment breakdown.

Electromechanical control of a lyophilization cycle has utilized cam-type recorder

controllers. However, newer units provide for microcomputer control of the freeze drying

process. A very basic requirement for a computer controlled process is a flow chart or logic.

Typically, operator involvement in a computer controlled lyophilization cycle primarily

occurs at the beginning. It consists of loading the chamber, inserting temperature probes in

product vials, and entering cycle parameters such as shelf temperature for freezing, product

freeze temperature, freezing soak time, primary drying shelf temperature and cabinet

pressure, product temperature for establishment of fill vacuum, secondary drying shelf

temperature, and secondary drying time.

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Leakage into a lyophilizer may originate from various sources. As in any vacuum chamber,

leakage can occur from the atmosphere into the vessel itself. Other sources are media

employed within the system to perform the lyophilizing task. These would be the thermal

fluid circulated through the shelves for product heating and cooling, the refrigerant employed

inside the vapor condenser cooling surface and oil vapors that may migrate back from the

vacuum pumping system.

Any one, or a combination of all, can contribute to the leakage of gases and vapors into the

system. It is necessary to monitor the leak rate periodically to maintain the integrity of the

system. It is also necessary, should the leak rate exceed specified limits, to determine the

actual leak site for purposes of repair.Thus, it would be beneficial to perform a leak test at

some time after sterilization, possibly at the beginning of the cycle or prior to stoppering. The

time and frequency for performing the leak test will vary and will depend on the data

developed during the cycle validation.

In order to minimize oil vapor migration, some lyophilizers are designed with a tortuous path

between the vacuum pump and chamber. For example, one fabricator installed an oil trap in

the line between the vacuum pump and chamber in a lyophilizer with an internal condenser.

Leakage can also be identified by sampling surfaces in the chamber after lyophilization for

contaminants. One could conclude that if contamination is found on a chamber surface after

lyophilization, then dosage units in the chamber could also be contaminated. It is a good

practice as part of the validation of cleaning of the lyophilization chamber to sample the

surfaces both before and after cleaning.

Because of the lengthy cycle runs and strain on machinery, it is not unusual to see equipment

malfunction or fail during a lyophilization cycle. There should be provisions in place for the

corrective action to be taken when these atypical situations occur. In addition to

documentation of the malfunction, there should be an evaluation of the possible effects on the

product (e.g., partial or complete meltback. Refer to subsequent discussion). Merely testing

samples after the lyophilization cycle is concluded may be insufficient to justify the release of

the remaining units. For example, the leakage of chamber shelf fluid into the chamber or a

break in sterility would be cause for rejection of the batch.

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FINISHED PRODUCT TESTING FOR LYOPHILIZED PRODUCTS

There are several aspects of finished product testing which are of concern to the lyophilized

dosage form. These include dose uniformity testing, moisture and stability testing, and

sterility testing.

(a) Dose Uniformity

The USP includes two types of dose uniformity testing: content uniformity and weight

variation. It states that weight variation may be applied to solids, with or without added

substances, that have been prepared from true solutions and freeze-dried in final containers.

However, when other excipients or other additives are present, weight variation may be

applied, provided there is correlation with the sample weight and potency results. For

example, in the determination of potency, it is sometimes common to reconstitute and assay

the entire contents of a vial without knowing the weight of the sample. Performing the assay

in this manner will provide information on the label claim of a product, but without knowing

the sample weight will provide no information about dose uniformity. One should correlate

the potency result obtained form the assay with the weight of the sample tested.

b) Stability Testing

An obvious concern with the lyophilized product is the amount of moisture present in vials.

The manufacturer's data for the establishment of moisture specifications for both product

release and stability should be reviewed. As with other dosage forms, the expiration date and

moisture limit should be established based on worst case data. That is, a manufacturer should

have data that demonstrates adequate stability at the moisture specification.

As with immediate release potency testing, stability testing should be performed on vials with

a known weight of sample. For example, testing a vial (sample) which had a higher fill

weight (volume) than the average fill volume of the batch would provide a higher potency

results and not represent the potency of the batch. Also, the expiration date and stability

should be based on those batches with the higher moisture content. Such data should also be

considered in the establishment of a moisture specification.

For products showing a loss of potency due to aging, there are generally two potency

specifications. There is a higher limit for the dosage form at the time of release. This limit is

generally higher than the official USP or filed specification which is official throughout the

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entire expiration date period of the dosage form. The USP points out that compendial

standards apply at any time in the life of the article.

Stability testing should also include provisions for the assay of aged samples and subsequent

reconstitution of these aged samples for the maximum amount of time specified in the

labeling. On some occasions, manufacturers have established expiration dates without

performing label claim reconstitution potency assays at the various test intervals and

particularly the expiration date test interval. Additionally, this stability testing of

reconstituted solutions should include the most concentrated and the least concentrated

reconstituted solutions. The most concentrated reconstituted solution will usually exhibit

degradation at a faster rate than less concentrated solutions.

(c) Sterility Testing

With respect to sterility testing of lyophilized products, there is concern with the solution

used to reconstitute the lyophilized product. Although products may be labeled for

reconstitution with Bacteriostatic Water For Injection, Sterile Water For Injection (WFI)

should be used to reconstitute products. Because of the potential toxicities associated with

Bacteriostatic Water For Injection, many hospitals only utilize WFI. Bacteriostatic Water For

Injection may kill some of the vegetative cells if present as contaminants, and thus mask the

true level of contamination in the dosage form. As with other sterile products, sterility test

results which show contamination on the initial test should be identified and reviewed.

FINISHED PRODUCT INSPECTION - MELTBACK

The USP points out that it is good pharmaceutical practice to perform 100% inspection of

parenteral products. This includes sterile lyophilized powders. Critical aspects would include

the presence of correct volume of cake and the cake appearance. With regard to cake

appearance, one of the major concerns is meltback.Meltback is a form of cake collapse and is

caused by the change from the solid to liquid state. That is, there is incomplete sublimation

(change from the solid to vapor state) in the vial. Associated with this problem is a change in

the physical form of the drug substance and/or a pocket of moisture. These may result in

greater instability and increased product degradation.

Another problem may be poor solubility. Increased time for reconstitution at the user stage

may result in partial loss of potency if the drug is not completely dissolved, since it is

common to use in-line filters during administration to the patient Manufacturers should be

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aware of the stability of lyophilized products which exhibit partial or complete meltback.

Literature shows that for some products, such as the cephalosporins, that the crystalline form

is more stable than the amorphous form of lyophilized product. The amorphous form may

exist in the "meltback" portion of the cake where there is incomplete sublimation.

CONCLUSION

The lyophilized technique proved to be an advantage for development of stable injectable

dosage form as the moisture content of the formulation is greatly reduced thus enhancing the

stability of the product, ease of handling, rapid dissolution because of porous nature of the

cake and easier transport of the material during shipping.Thus above optimized formulation

was transferred from lab scale to commercial scale.

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