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What is Media Fill

The Media fill or Broth fill technique is one in which a liquid microbiological nutrient growth medium is prepared and filled in a simulation of normal manufacturing operation.

The microbiological growth medium such as Soybean Casein Digest Medium (SCDM) is processed and handled in a manner which simulates “normal” manufacturing process with same exposure and possible contamination.

The final container is then incubated and checked for turbidity which indicate the microbial contamination.

Medium Selection

• The medium should be able to support the growth of a wide range of microorganisms.

• The medium should be suitable from a process perspective to perform as product (e.g. it should be filterable, if the product is normally also filtered).

• The medium should be clear in order to be able to observe any turbidity caused by growth.

• The medium should be prepared according to manufacturer’s instructions.
• Medium tested on House Flora Meaning: House Flora determined as a prerequisite
• Growth Promotion Property tests with the correct amount of microorganisms (10 – 100 or less CFU/unit)
• GPP test performed either after processing or in parallel; growth within 5 days

Area General Principles :

• Media fills should be performed in the same areas as product fills (this includes being in and out a freeze-­‐dryer, if applicable!).
• If the same process is carried out in another clean room, this should also be validated.
• Each filling line to be validated twice per year
• Bracketing principles can be applied to reduce number of fills.
• Worst case principles can be applied to reduce number of fills.

Filling Equipment’s General Principles :

• The same equipment that is used for product fills should be used for media fills.

• If inert gases are normally used in the process, filtered air should be applied during media fills not to prohibit growth of microorganisms. (If anaerobic microorganisms are found during routine E.M., the use of inert gases should also be considered.)

• All aseptic holding vessels should be part of a regular process simulation test, unless a validated pressure hold or vacuum hold test is routinely performed.

Process General Principles :

• The media fills should simulate the complete product fill situation as far as equipment, processes, Environmental Monitoring, personnel involved, areas and time taken for both filling and holding.

• The media fill should represent a “worst case” situation compare to a normal fill with respect to manipulations and interventions.

• If filling takes place for over 24 hours, the media fills should extend to the same time, unless the validity of the media fill is not compromised by running the fill for less time.

PLANNED INTERVENTIONS

• Media fills should include all interventions normally expected during product filling.

• Unplanned interventions should reflect actual experience with the filling process.

• Simulating interventions defines the validated envelope– Excursions outside validated envelope, batch failure as default
• Normal actions associated with the process, e.g. stopper bowl filling
• Normal occurrences, e.g. needle exchange, line stoppage
• Abnormal occurrences determined from deviations noted during previous runs
• Operator versus allowable interventions by him/her to be defined
• During normal operation, after intervention: removal of possible contaminated vials; that is allowable for Media Fill as well.
• Only discarding of vials as it is usually done.

Media Fills Duration :

• ISO: “sufficient duration to cover most manipulations”
• EU: “sufficient to enable a valid evaluation”

• PIC: “Over the whole of the standard filling period”
• FDA: “Duration of commercial aseptic process best and preferred for larger simulations

PRIMARY PACKAGING COMPONENTS – GENERAL PRINCIPLES

• Primary packaging components should be prepared as for regular production.

• When normally opaque containers are used, these should be used for media fills as well. The examination of growth though should be performed by transferring the whole contents.

PRIMARY PACKAGING COMPONENTS – Point to consider

• Primary packaging components should be the same as for normal production runs (amber vs clear vials?)

• Primary packaging components should be prepared the same as for normal production runs (washing and sterilisation)

• Media fill volume should be sufficient to cover, when the vial is inverted, the whole inner surface.

Frequency :

• Start-­‐up simulation is applicable to new processes, new equipment or after critical changes to environment, equipment, process or significant personnel changes.

• Start-­‐up simulation should consist of three consecutive, satisfactory runs with the same shift of people.

• Ongoing simulations should happen normally twice a year per shift and per process (unless there were changes to the product process or action limits exceeded).

The Outcome :

• Incubation is normally 14 days at 20 – 25ºC or sometimes 7 days at 20 – 25ºC followed by 7 days at a higher temperature (<35º C).

• When inspecting for growth, a known sterile container should be used as comparison.

• Alert and actions limits should be previously established.

• Even if not alert nor action limit was exceeded, microorganisms should be identified.

Media Fills – OOS

• There are not detailed indications from regulations, except:
• Each contamination must be investigated.
• Repeat media fill or repeat validation, after investigation, depending on the level of contamination and the run size.

• There is not distinction between initial validation and routine revalidation

Media Fills—Points to consider in Summary :

• Duration of longest run
• Worst case environmental conditions
• Number and type of interventions, stoppages, adjustments, transfers
• Aseptic assembly of equipment
• Number and activities of personnel
• Number of aseptic additions
• Shift breaks, changes, multiple gownings
• Number/type of aseptic equipment disconnections and connections
• Aseptic samples
• Line speed/configuration
• Manual weight checks
• Operator fatigue
• Container/Closure types run on the line
• Temp/Relative humidity extremes
• Conditions permitted before line clearance

General Pattern:

• Locate the problem by ranking possible causes.
• Verify the presence of the most probable cause.
• If present – fix the problem, otherwise verify the existence of the next possible cause.

First try to distinguish System problem or Method Problem

HPLC System Components

• Pump

• Injector/ Autosampler

• Column

• Detector

• Data System/Integrator

Method vs. System Troubleshooting

System Parameters

• Flow stability
• Backpressure
• Clogging
• Detector problems
• Injection suitability

Method Parameters

• Flow rate
• Eluent composition
• pH &pH modifier (type)
• Injection volume
• Temperature
• Gradient profile

System Parameters

Simple preliminary verification of system setup can save time

Solvent	Degasser	Pump	Auto sampler	column	Detector
Bottle fill-in Inlet filter date	Flush if solvent change >15 mL	Back pressure Flow stability Check-valves	Vial fill-in connections cross-contamination	Column type connections	Wavelength

Categories of Column and System Problems

• Pressure

• Peak shape

• Retention
• Detection

I. Pressure Issues

Column observations	Potential Problems
High pressure	Plugged frit Column contamination Plugged packing
Low pressure	Leak Flow Incorrect

Determining the Cause and Correcting High Back Pressure

Many pressure problems are due to blockages in the system.

If Column pressure is high:

• Back flush column – Clear “dirty” frit surface
• Wash column – Eliminate column contamination and plugged packing
• – high molecular weight/adsorbed compounds
• – precipitate from sample or buffer

Column Cleaning

Flush with stronger solvents than your mobile phase

Use at least 25 mL of each solvent for analytical columns

Reversed-Phase Solvent Choices in Order of Increasing Strength

• Mobile phase without buffer salts
• 100% Methanol
• 100% Acetonitrile
• 75% Acetonitrile:25% Isopropanol
• 100% Isopropanol
• 100% Methylene Chloride*
• 100% Hexane*

* When using either Hexane or Methylene Chloride the column must be flushed with Isopropanol before returning to your reversed-phase mobile phase.

Prevention Techniques for column problems

Use column protection

• In-line filters

• Guard columns

• Filter samples
• Filter buffered mobile phases

• Sample clean-up (i.e. SPE)

• Appropriate column flushing

II.           Peak Shape Issue

What Are Common Peak Shape Issues?

1. Split peaks
2. Peak tailing
3. Broad peaks

• Many peak shape issues are also combinations – i.e. broad and tailing or tailing with increased retention
• Symptoms do not necessarily affect all peaks in the chromatogram

• Each of these problems can have multiple causes

Peak Splitting Caused By Disrupted Sample Path

• Flow Path Disrupted by Void
• Sample Allowed to Follow Different Paths through Column
• Poorly Packed Bed Settles in Use
• High pH Dissolves Silica

Split Peaks from Column Contamination

Column: Stable Bond SB-C8, 4.6 x 150 mm, 5 μm Mobile Phase: 60% 25 mM Na2HPO4, pH

3.0 : 40% MeOH Flow Rate: 1.0 mL/min

Temperature: 35°C Detection: UV 254 nm Sample: Filtered OTC Cold Medication:   

1.Pseudoephedrine 2. APAP 3. Chlorpheniramine

Peak Tailing, Broadening and Loss of Efficiency

May be caused by:

• Column “secondary interactions”

• Column contamination

• Column aging

• Column loading

• Extra-column effects

Peak Tailing – Column Contamination

Trick: Reverse Column and Run Sample –If Improved, Possible Cleaning Will Help -No improvement-Column Damaged and Needs to be Replaced

Peak Shape: Fronting Peaks

Causes: Column Overload

Peak Shape: Broad Peaks

All Peaks Broadened:

• Loss of Column Efficiency.
• Column Void.
• Large Injection Volume

Some Peaks Broadened:

• Late Elution from Previous Sample (Ghost Peak).
• High Molecular Weight.
• Sample – Protein or Polymer.

III.   Changes in Retention Time

Changes in Retention Can Be Chemical or physical May be caused by:

• Column aging

• Column contamination

• Insufficient equilibration

• Poor column/mobile phase combination

• Change in mobile phase

• Change in flow rate

Mobile Phase pH and pH Buffers Why Are These So Important in HPLC?

pH Effects Ionization

• Silica Surface of Column
• Sample Components of Interest

Buffers

• Resist Changes in pH and Maintain Retention
• Improve Peak Shape for Ionizable Compounds

Effects Column Life

• Low pH strips Bonded Phase
• High pH Dissolves Silica

Importance of pH and Buffers

• pH is an effective tool for adjustment of selectivity and retention

• pH can be used to optimize the resolution

• Reversed phase packaging are most stable between pH’s 2 – 8.

• Don’t Forget – Match Column to pH of mobile phase for maximum column lifetime.

IV. Detection Issues

Recognize Where the Problem Originates

• Is it a consequence of technique?

• Is It expected due to use of certain mobile phase components?

• Can it be corrected by adjusting detector parameters?

Drifting Baselines

• Detector (UV) not set at absorbance maximum but at slope of curve
• Gradient Elution

• Temperature Unstable (Refractive Index Detector)

• Contamination in Mobile Phase

• Mobile Phase Not in Equilibrium with Column

Baseline Noise

Conclusions

HPLC column problems are evident as

• High pressure (prevention better than the cure)
• Undesirable peak shape
• Changes in retention/selectivity

Often these problems are not associated with the column and may be caused by instrument and chemistry issues.

• pH of mobile Phase
• Instrument Connections
• Detector Settings
• Metal Contamination

User requirement specification (URS) is a list of all the requirements from the user, like equipment to be purchased. After the preparation of the list, the documents are sent to the manufacturer to get the required materials as per the given criteria.

The user department will raise the indent for his requirement regarding machine equipment or software. He/She will give all the requirements in the format of URS, which include the functional and technical specifications for the machine equipment or software. This specification in the written format is defined as URS. It shall be very specific.

There should not be any confusion during the preparation for approval. Functional as well as technical aspects shall be clearly mentioned. The number of spare change parts required shall be mentioned in URS.

Users should also give the details of other areas which are going to affect if the machine is procured or which are the other areas that need to modify such as the environmental (AHU) control system. Also, keep in mind whether this modification is possible and feasible; is it going to impact the other existing system. URS is a supporting document for the preparation of design qualifications.

User requirement specification for equipment.

The following point must be included in URS:

• Name of the user department
• Location
• machine/equipment/software name
• Purpose of the machine/equipment/software
• Other areas of impact (AHU, movement, and space)
• Parameters to be considered for the URS.
• Model making Name with specification, and quantity with the remark.
• Capacity: give the detailed specification and quantity likes requirement in Kilogram or liters.
• The material of construction: give details about the material of construction like Stainless steel and its grades.
• Give details about Instruments on machine likes Metal detector, Camera inspection system, and pinhole detector, etc.
• Required calibration details with the specification with remarks
• Details specification: baffles, Dia, punches, Guide track, cutter, and channel.
• Specified details about required tools
• Documentation like  Qualification/ manuals
• Environmental: (Include the temperature and humidity of the area ) / health safety requirements (like MCB and safety Guard) and Control (Specify needs of equipment, interfaces, output forms (e.g., USB)
• Critical control points
• Others:
• Utilities. Utilities. Define the kind of power supply to use for the equipment, the requirement of UPS, or other utility requirements. Include water system, quality, or compressed gas, if required.
• Availability. Limitation of operation time for the equipment
• Supporting Documents. Operating manuals, warranty, parts, spare parts, circuit diagrams.
• User requirement specification document Shall be signed by an authorized person in the column prepared by, reviewed by, and approved by. In the end, review, revise, and approve the URS. The next step is the design qualification.

Conclusion : When a system is being created, User Requirements Specifications are a valuable tool for ensuring the system will do what users need it to try to do.