Lyophilized Drug Product Cake Appearance What Is Acceptable

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For Preparation Of Ph Sensitive Hydrogel With Controlled Deliveryof Antibiotics

Introduction to Lyophilization

4. For manufacturing of probiotic chewabletablet- A new freezedrying model is designed for the preparation lactic acid bacteria freeze dryingpowder centrifuge. This freeze-dried powder is used for the preparation of probioticchewable tablet. The new model consists of a bottom plate, drying bottle, feed hopper, centrifuging chamberand cabinet.43

Why The Excipients Are So Important In A Lyophilized Formulation

A correctly lyophilized cake needs to have uniform appearance, well stocked to the walls of the vial without falling off from it. It should not have cavities at the bottom and the color should be uniform all around the lyophilized cake, maybe presenting slight differences because of the crystals formed during the freezing steps, being dendritic or very small and amorphous.

Lyophilized formulation is designed around its API and in most of the cases include a number of excipients, such as buffers, stabilizers, bulking agents and tonicity modifiers. So we can say that a well-chosen excipient formula can prepare a lyophilized product for a long shelf-life and a stable level of biological activity. Excipients are the integral part of pharmaceutical product development to achieve the desired product profile .

The main goal of the lyophilized formulation it is to have the formulation as simple and stable as possible while reaching acceptable chemical, physical, and microbiological stability.


In many pharmaceutical formulations, buffers are used to stabilize pH. Choosing a correct buffer is especially crucial in lyophilized formulations, since some buffers can undergo dramatic pH shifts during the freezing process. Regardless of buffer selection, the concentration of buffer used in lyophilization should be reduced to the minimum amount needed to control pH in order to prevent instability resulting from concentrated regions during the lyophilization process.

Bulking agents

What Is Acceptable Appearance In Lyophilized Products

Hello folks,

Working with lyophilized products is always interesting. If lyo cycle went well and everything goes fine then no issues. But, Lyophilization is more tricky when unexpected variations happened during lyo cycle. This results in different kinds of issues majorly, related to appearance of product.

Normally, after lyophilization the resulting product may be an intact cake or powder or some kind of flakes depending on the type and concentration of ingredients in the formulation. During visual inspection, there will be collection of acceptable appearance vials along with separation of vials with defects. So, it is important to determine which cake is acceptable and which is not. Sajal patel have published a wonderful article about what is an acceptable cake after lyophilization and what is not acceptable.

Let us have a look at few cakes with issues.

After lyophilization, drug products are subjected tovisual inspection. These visual inspection parameters includecake appearance, extraneous particulate matter, and assessment of minor, major, and critical defects of the lyophilizeddrug product. The appearance of an ideal lyophilized cakeshould be uniform and elegant without any defects andshould have adequate mechanical strength to avoid cakedisruption during handling and distribution.

Collapsed cake:

Left vial: Complete collapse, Centre vial: Partial collapse, Right vial: No Collapse.
various degrees of cake collapse during storage under stressed conditions.

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Validation Approaches To Freeze

Emerging and Existing Container Closure Systems

Dual-chamber containers , syringes , and cartridges ) are emerging container closure systems developed to improve patient convenience during administration. The benefits of dual-chamber systems also include increased patient safety , decreased dose administration errors , and cost reduction due to no need for separate diluent containers .

Stage 3continued Process Verification

Lyophilized Drug Product Cake Appearance: What Is Acceptable?

The third and final stage of process validation is to continuously monitor the performance of the lyophilization process during the manufacturing of the subsequent commercial batches to confirm that the process remains within the validated operating ranges that would yield consistent product quality. This is achieved by establishing an ongoing process to collect and analyze data of the incoming raw materials, the finished drug product, and the process data that are deemed relevant to product quality. The data collection and analysis should be executed following robust statistical methods as well as appropriate qualitative approaches. Additionally, the qualification of the lyophilization equipment should be performed periodically to ensure that the process performance remains within the validated limits. Qualification, or re-qualification, of equipment, is generally only done on a per cause basis. For example, calibration checks are done as per performance rather than for continued process verification management. Qualification is performed as part of IQ/OQ and not each time PPQ runs are done. As such, requalifications are done based on the site validation master plan and change management procedures. In cases where qualifications are not done, the rationale should be provided.

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Monoclonal Antibody Case: Fill Volumes And Equipment Validation Strategy

A commercial monoclonal antibody lyophilized product with two different vial strengths is to be transferred within the same commercial manufacturing site to a different suite, resulting in a change of filling line and lyophilizer equipment. Besides, the new suite has two different lyophilizers that would be used to manufacture the product. The PPQ protocol in the new suite consisted of four runs in total with two batches per product strength: three validation batches to be manufactured in one lyophilizer to demonstrate batch-to-batch consistency and a fourth validation batch to be manufactured in the second lyophilizer to demonstrate the equivalent performance of the two lyophilizers. The protocol requires that lyophilization process validation should be conducted under anticipated commercial manufacturing conditions. Performance qualification of critical processing equipment was conducted to verify that the equipment performed consistently within defined operating parameters when subjected to normal production conditions. Heat and moisture mapping studies were performed to demonstrate that the two lyophilizers were functionally equivalent. The operational process steps for the manufacturing of both strengths were similar, and the vial size and composition were the same for both product strengths the only difference was in their respective filling volumes.

Table XII Process Validation Matrix

Current Practices In Lyophilization Process Validation

PPQ of lyophilization , like many other processes, has historically relied on the three-drug product lot validation for a given cycle and dose where the validation consists of repeating the process in three consecutive batches of product for a given product image. This is coupled with expanded sampling for critical quality attributes that are most impacted by the lyophilization process, e.g., visual appearance, residual moisture, potency, and reconstitution time. Although the FDA has provided inspection guidance on lyophilization , it does not include great detail about PPQ runs, as the guidance predates the current three-stage validation model. To benchmark and understand the current validation practices, Lyophilization Technology Hub , an industry-academia consortium to advance the science and technology of lyophilization, surveyed its industry members that confirmed these practices continue today .

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Api: Active Pharmaceuticalingredient Tga: Thermogravimetricanalysis Ich: International Councilfor Harmonisation Rna: Ribonucleic Acid Nara: Nationalarchives And Records Administration Pvp: Polyvinylpyrrolidone


1. Liu Y., Zhao Y., Feng X., Exergy analysis for afreeze-drying process, Appl Thermal Eng, 2008, 28, 675690.

2. Khairnar S, Kini R, HarwalkarM, Chaudhari SR., A Review on Freeze Drying Process of Pharmaceuticals, InternationalJournal of Research in Pharmacy and Science, 2014 Jan 1 4.

3. Louis Rey PhD et al., Sage of freeze drying CH-1010.5-8.

4. Shukla S. Freeze DryingProcess: a Review, International Journal of Pharmaceutical Sciences andResearch, 2011 Dec 1 2:3061-8.

5. Nail SL. et al.Fundamentals of freeze-drying, Development and Manufacture of ProteinPharmaceuticals. Marcel Dekker, 2002 281360.

6. Nireesha GR, Divya L,Sowmya C, Venkateshan NN, Babu MN, Lavakumar V. Lyophilization/freeze drying-anreview. International Journal of Novel Trends in Pharmaceutical Sciences, 2013Oct 4 3:87-98.

7. Chien and Yiew W. Pharmaceutical Dosageforms: ParenteralMedications. Indian Journal of Pharmaceutical Science and Technology, 1981, 35,106-118.

8. Khandagale P.M., Bhairav B.,Saudagar R.B., Lyophilization Technique: A Review, Asian Journal of Research inPharmaceutical Science. 2016 6 269-76.

9. Shivanand A., MukhopadhayayaS., A Review on Lyophilization: A Technique to Improve Stability ofHygroscopic, Thermolabile Substances. PharmaTutor,2017, 5 28-39.

10. Gaidhani K.A., Harwalkar M.,Bhambere D., Nirgude P.S., Lyophilization/ freeze dryinga review. World Journalof Pharmaceutical Research, 2015, 4 516-543.

Received on 23.08.2019 Modified on 06.10.2019

Stage 2process Performance Qualification

Lyophilization/Freeze Drying of Mannitol vs Pure Water (time-lapse of 20 hour process)

PPQ is the second part of stage 2 of process validation. According to FDA Guidance 2011, Process Validation: General Principles and Practice , the goal of PPQ is to demonstrate that the commercial manufacturing process performs as expected and confirms process design through the use of the following five elements qualified facility and utilities, equipment and components trained personnel, well-understood manufacturing process, and control procedures . Successful completion of PPQs is required before commencing commercial production of the drug product batches. The approach for PPQ should be based on manufacturers sound scientific understanding of the product and manufacturing process and its relation to the combined use of the five elements mentioned above. Manufacturing conditions during PPQs are often based on an understanding of the qualified scale down process models and the cumulative data generated during clinical manufacturing and small scale, pilot, and commercial-scale studies. It is expected that PPQ will involve extensive sampling, additional testing, and higher scrutiny to ensure homogeneity in drug product quality throughout the batch. The duration to continue extensive sampling and additional testing should be based on a continued process verification program which includes considerations for the volume of production, process complexity, understanding of the process, and experience with similar products and processes .

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Uneven Distribution Or Settling Of The Lyophilized Cake May Point Back To Issues In The Drying Phase Or Problems With The Cake Formulation

Uneven distribution or settling of the lyophilized cake may point back to issues in the drying phase, or problems with the cake formulation.

During the primary drying phase, lyophilized cake powder may sometimes be partially blown out of the vial. This may happen due to melting, but a more common cause is an issue with the cakes formulation, resulting in a cake matrix that lacks the cohesion to withstand the force of escaping water vapor. This is particularly common with formulations containing organic solvents or low levels of total dissolve solids. It should be considered a serious issue, as partially ejected cake matter can compromise the vials seal.

Dried product can also accumulate between the vial and stopper if droplets are left around the stoppers neck during initial filling. This residual material then solidifies throughout the freeze-drying process, compromising the integrity of the seal as it expands and contracts in response to shifts in temperature and dryness. Since dried product between the vial and stopper poses a serious risk to product integrity, any vials presenting this issue will have to be discarded.

Importance Of Residual Moisture

Drug product formulations for many types of molecules are not stable in aqueous solution and often require refrigerated or frozen conditions or the addition of excipients to prevent degradation. Protein and mAb formulations are particularly susceptible to aggregation, deamidation, oxidation, and other degradation pathways not only in solution, but as freeze-dried solids. Residual moisture acts as a plasticizer in predominantly amorphous systems and lowers the glass transition temperature, Tg, of the formulation . Even relatively small changes in residual moisture can lead to significant changes in both physical stability and solid-state chemical stability. These types of degradation are more likely to occur with higher levels of water in the formulations therefore, lyophilization is an appropriate processing step to remove moisture from the formulation.

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Use Of Run Or Control Chart

A run chart shows a general trend of a process parameter over time. For example, for chamber pressure, it can be the data collected every minute over the different stages of the lyophilization cycle. For multiple batches manufactured in a year, a run chart can be constructed by plotting maximum and minimum values of the chamber pressure for each batch. Different options for plotting a run chart are provided in the section below.

Figure 1 depicts a hypothetical example of a trend chart for minimum and maximum chamber pressures for each of the 30 batches of a drug product. As a worst case, 010% variability relative to a set point pressure of 100 mTorr was randomly applied to each of the 30 batches. UCL and LCL were calculated using average±3×standard deviation in pressure data for 30 batches. Note that the USL and LSL of 120 and 80 mTorr are acceptable process parameter limits derived from lyo process robustness studies performed during stage 1process design of the process validation. For demonstration purposes, pressure data for batches 2 and 3 were shown to be slightly outside the UCL and LCL, respectively.

Fig. 1

HypotheticalFi trend chart for chamber pressure for 30 drug product batches. Legend: Min=minimum chamber pressure for each batch Max=maximum chamber pressure for each batch UCL=upper control limit LCL=lower control limit USL=upper specification limit LSL=lower specification limit

Bubbles Rings Meltback And Other Residue Inside The Vial May Indicate Flaws In Freezing And/or Drying

Lyophilized Drug Product Cake Appearance: What Is Acceptable?

Lyophilized cakes that are slanted, cracked, or otherwise physically damaged may be indicative of issues with the loading or transportation processes.

When a small amount of eutectic melting occurs during the drying stage, the solution becomes saturated with air, resulting in the formation of small air bubbles within the concentrate during freezing. These air bubbles may then expand, rising to the surface of the solution and if the formulations chemical properties cause them to remain structurally stable during drying, they may give the cake a puffed appearance. The pharmacological impact of cake puffing is not well-studied however, entire batches of puffed cakes may be indicative of a mechanical problem.

Some cakes, on the other hand, may appear shrunk, having pulled away from the walls and bottom of their vials. This appears to be correlated with an abnormally high amount of unfrozen water during the freezing stages, which evaporates during the drying stages, contracting the volume of the cake. When the vials and handled, the structural stress within the cakes causes them to crack.

If some of the solution fails to drip all the way down to the bottom of the vial before freezing is complete, or the vials are excessively agitated after filling, they may display the distinctive lyo ring of residue after drying. While the lyo ring may not impact product quality, it may be indicative of poor handling, or inadequate control of the fill/finish stage.

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Dual Chamber Syringes And Cartridges

During the administration of the drug product that is filled into the DCSs/DCCs, a plunger rod attached to the second stopper is used to press the stopper and move the diluent toward the middle stopper. The middle stopper is then moved, opening a bypass for delivering the diluent to the drug product compartment. After complete reconstitution, the solution can be directly administered to the patient no additional steps are needed.

Lyophilized Cakes That Are Slanted Cracked Or Otherwise Physically Damaged May Be Indicative Of Issues With The Loading Or Transportation Processes

Many other cake malformations can result from a wide variety of mechanical issues at various stages of the manufacturing process. One of the simplest and most common issues is slanting: cakes come to rest at an angle within their vials. This typically occurs when some vials within a cluster lose contact with the shelf. It can create serious problems with product stability, however, as slanted cakes may dry with higher residual moisture then their non-slanted counterparts.

In some cases, a film may form on the interior surfaces of vials. While this fog might at first glance appear to be related to excess water vapor or improper drying conditions, it more frequently results from agitation of the vials contents as they are loaded into the lyophilizer. Because fogging can lead to buildup of residue around the seal of the vial, it is a cause for serious concern, and must be addressed by taking handling vials more gently during loading.

Breaking, chipping and dusting of cakes are also typically indicative of problems with handling particularly if the product that emerges directly from the lyophilizer appears uniform and evenly settled. Transportation stresses frequently fragment cakes, causing them to arrive at their destinations with dust or chips that were not present at the manufacturing facility. Although minor dusting and chipping may not impact product quality, distributors should be cautioned to avoid unnecessary agitation during transport.

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Many Types Of Cake Appearance Flaws Can Indicate Missteps In The Manufacturing Pipeline

While lyophilized drug products are typically not intended for consumer display, the composition of their final cakes can still play a major role in their success or failure in the marketplace. In fact, some flaws in cake appearance actually can have clinical impacts for example, product caught between the vial and stopper may indicate compromised sterility, as well as inconsistent doses between vials.

In addition to clinical hazards like these, non-uniform cakes can result in serious concern on the end users part. When cake appearance fails to align with the description on the packaging, clinics and other users may well lodge complaints with the manufacturer, expressing worry about poor-quality manufacturing . Indeed, inspectors in certain markets closely examine the cake appearance of every product they plan to purchase. In these cases, non-uniform or otherwise flawed cakes may inhibit regulatory approval, or even prevent access to those markets altogether.

For all these reasons, the formulation and final appearance of lyophilized cakes is far more than just a cosmetic issue. All the following issues with cake formation may indicate significant issues with the formulation or good manufacturing practices somewhere in the manufacturing pipeline, and are deserving of careful analysis.

The Right Equipment For Your Freeze Dryer

Visual Inspection of Lyophilized, Suspension, Emulsion Products, Amber/Opaque Container @PHARMAVEN

Ellab recommends performing a qualification of your process under one of the following conditions:

  • Your internal SOP requires it
  • You have installed a new system
  • You have implemented major changes to your system
  • You have had to relocate your setup
  • Your process has not been qualified for 6-12 months

Performing the appropriate qualifications is one thing, but having the right equipment to do the job can be a science in of itself however, it doesnt have to be. With reliable products like:

  • LyoPro data logger: Eliminate data gaps and stay FDA compliant with a data logger designed to perfectly fit any vial size and freeze dryer
  • TrackSense Vacuum Sensor: Ensure the integrity of your chamber throughout the entire process
  • TrackSense Thermocouple Sensor: Get a high-powered device equipped with ultra-thin sensors that ensure next to no impact on the sample.

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