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.

Introduction :
This chapter defines the requirements for good documentation practices which build a basic foundation for a good quality management system. Good documentation practices are those measures that collectively and individually ensure documentation, whether paper or electronic, is secure, attributable, legible, traceable, permanent, contemporaneously recorded, original, and accurate.
Good documentation practices follow to protect the integrity and quality of all documents/records, electronic and handwritten, used in different GMP operations and activities and ensures these records are truthful, readily retrievable and traceable.
General Requirements for GMP Documentation :
This chapter covers different levels and types of GMP documentation, including paper and
electronic records related to manufacturing, testing, packing of pharmaceutical products, APIs,
excipients, dietary supplements, food ingredients and medical devices.
These documents and records consist of raw data, reports, protocols, procedures, deviations, investigations, batch records, formats, and records related to trainings, equipments and retention for manufacturing and analytical controls.
Data integrity should always be given utmost importance which means the extent to which all data is complete, consistent and accurate throughout the data life cycle. Controls should be in place and any data integrity incident, if noticed; an appropriate corrective action should be taken to prevent recurrence of the same. Attempts to cover-up mistakes are considered as ‘data integrity’ issues and should be prohibited at all levels.
Principles :
Personnel should be kept up to date about the application of good documentation practices (GDP) to ensure that the principles of ALCOA and ALCOA-plus are understood and applied to electronic data in the same manner that has historically been applied to paper records. Good documentation requirements for manual and electronic records include the following, as applicable;
ALCOA:

A commonly used acronym that all records and data should be attributable, legible, contemporaneous, original and accurate.
ALCOA-plus:

A commonly used acronym for “attributable, legible, contemporaneous, original and accurate” data, which puts additional emphasis on the attributes of being complete, consistent, enduring and available – implicit basic ALCOA principles.

Attributable:

Attributable means information is captured in the record so that it is uniquely identified as executed by the originator of the data (e.g. a person or a computer system). Original data and further amendment if any should be traceable with respect to person, date and time, reason with signatures and in summary audit trails.

Legible:

The terms legible refers to the requirements that data is clear, easily understandable, and free from overwriting and unauthorized changes, and allow a clear picture of the sequencing of steps or events in the record so that all activities conducted can be fully reconstructed by the people reviewing these records at any point during the records retention period set.

Contemporaneous:

Data should be recorded concurrently at the time of performing the activity and recordings such as in-process, environmental should maintain as and when an activity is carried out along with signatures, date and time.
Original:

Data should be recorded originally, not entered on a piece of rough paper and then copied, no trial injections. OOS results should be reported immediately and data should not be newly created or rewritten after corrections and cancellations.

Accurate:

The term “accurate” means data should be correct, truthful, complete, valid and reliable. Data should not be falsified and fabricated.
Laboratory Records :
 System must have a collection of technological & procedural controls to protect data within the system to ensure that all records are authentic, incompatible and (where applicable) confidential. In lab situation this include lab results used to determine quality, safety, strength, efficacy or purity and in manufacturing this includes all decisions related to product release and product quality.
 Controls should be in place, needed for the identification, storage, protection, back-up, archive, retrieval, retention time, and disposal and to protect the integrity of its records.
Access to these records should be consistent with confidentiality and records should be readily available.
 All Technical activities should be carried out with valid, correct and current effective versions of instruction documents and recording formats should have an identification number and a version number (where appropriate), allowing the sufficient space to record entries etc.
 Original observations, data, and calculations should be recorded at the time of activity performed, without any bias or prejudice. These records also include the identity of personnel responsible for the performance of activity.
 Automated data capture or printers should be attached and connected to equipment, such as balances, to ensure independent and timely recording of the data. User access rights to automated systems should be restricted to prevent data amendments (or audit trail).
 Ability to change any clock used for recording timed events, for example, system clocks in electronic systems and process instrumentation should be restricted.
 Pre-dating that is, signing for an activity in advance or post-dating (back dating that is, signing for an activity with a back-date) either documents or corrections should be strictly prohibited.
 Impermanent records like data printed on thermal paper, etc. should be copied on to a permanent medium, and the copies should be attached to, or stored along with the original signed records.
 All error rectifications / filling of missed entries should be traceable to the person who made
the entry, irrespective of the stage at which the error has been noticed.
 All Documents / records should have page numbers (preferred format: ‘Page X of Y’). All master documents should be typed or pre-printed. Hand-written documents should not be used as master documents.
 Pens with indelible ink / Ball pen(only blue colors)should be used for recording of entries and for signing off any kind of documents. All entries and records should be concise, legible, unambiguous and accurate.

Data Collection and Recording :
 Good data and records management practices are critical elements of the quality system and a systematic approach should be implemented to provide a high level of assurance that throughout the product life cycle, all GMP records and data are complete and reliable.
 Laboratory information management system(s) (LIMS) includes the management of data and information contained in both computerized and non-computerized systems should be well defined in quality standard procedures.
 The computerized laboratory information management system used for the collection, processing, reporting, storage, retrieval of data should be validated for functionality before introduction and any subsequent changes should be validated before implementation.
 Technical records of original observations, derived data and enough information to establish an audit trail, calibration records, staff records and a copy of each CoA should be retained for a defined period as applicable.
 Amendments to technical records should be traceable to previous versions or to original observations. Both the original and amended data and files should be retained including the date of alteration, an indication of the altered aspects and the personnel responsible for the alterations.
 Handwritten records should be signed or initialed and dated at the time the information is entered. All entries related to analysis being performed should be done in chronological order. In case continuous pages of a notebook are not being used to record data, continuity should be denoted by mentioning the reference of the notebook number or page numbers at appropriate places. For example, if experiment is recorded in a laboratory notebook on Page 25 and calculations are recorded on Page 35, cross reference of the same should be given on both pages.
 All Instruction documents should have the effective date printed or stamped on them. All dates should be expressed in a format that clearly indicates the day, month and year. Time should be preferably recorded in the 24 hrs format as HH:MM. In case, date and time is printed from a machine or a computer, the date and time format of the instrument/machine should be followed and reviewed periodically for any discrepancy.
 Blank spaces or pages should have a single slanting line from start to end with a signature and date and the reason for the page being blank (e.g. ‘Not Applicable’ or ‘NA’ or N/A).
 If any column or row or cell is Not applicable, “NA” or N/A” should be entered in the space provided in the format.
 Only validated excel sheets should be used for calculations. Wherever such excel sheets are not available, calculations should be re-verified with validated calculators. In case of analysis, step-by-step details of the testing procedure, dilutions, critical test parameters, etc. as required by the standard procedures should be documented concurrently in Analytical Raw data sheet and laboratory Logbooks. All printouts, chromatograms, spectrum, records of analysis, etc. should be duly signed with date by the activity doer person, immediately after the activity is performed.
 All invalidated/disregarded Chromatograms should have a justification written by the ‘Doer’ with signatures and approved by in- charge.
 Decimals less than one should be preceded by a Zero. Rounding Off’ of numerical values during analysis should be followed as under calculation of results in general notices. In case readings or values are to be recorded from digital electronic displays, same values or readings should be transcribed from system to documents.

 Processing of chromatograms in chromatographic analysis should be done within 24 hours of completion of analysis sample set, with exception allowed in case of holiday. If the concerned analyst is unable to attend duty on the next working day, the task should be allocated to another analyst for processing of the chromatogram. However, in any rare case after processing of chromatogram the printout is not being taken within 24 hrs it may be taken within next 24 hrs after approval and proper reasoning.

Data Reviewing and Reporting :
 Specimen signatures, initials record of each employee involved in GMP documentation should be maintained to use for traceability of signatures for all the records. Signatures essentially mean that the signatory is responsible for the accuracy of data and information for the activity being signed for. Hence, the signatory should confirm the accuracy and completeness of information and data before signing.
 All GMP records should be appropriately reviewed and signature by a second person to confirm the accuracy, compliance and completeness of the work done.
 A single person should not sign for multiple roles for the same activity or entry. e.g. A doer cannot be the ‘Verifier’ / ‘Reviewer’ / ‘Approver’ for the same activity or entry recorded. No employee is authorized to sign for an activity performed by another employee.
 Persons preparing, reviewing or approving documents or persons recording, verifying or approving records should be on the basis of SOPs as accountability steps for different levels of review. All document signatories should be adequately trained for the activity performed by them.
 Attachments to a document should have reference of the parent document, and the parent
document should have details of the attachments. In case of electronic records, all child records of a parent document should have an indication of the relationship with the parent document. Data should be recorded directly on only approved and authorized formats (e.g. Logbooks, Raw Data Sheets and other similar records). Analysis data documentation should not be recorded on unauthorized documents e.g. scrap papers, note pads, rough register and other similar items.
 In case a sample has been analyzed by two or more analysts for different tests, each analyst should complete the test & related documentation for respective tests and sign (with date) his or her part. The analyst to whom the sample was issued originally should preferably sign (with date) the CoA; if this is not possible, another suitable analyst or department In charge should prepare & sign the CoA and submit it to a Reviewer. The reviewer should ensure that all tests as per specification have been carried out as per
applicable testing procedures and results are documented.
 Analytical results for specific batch of a sample are compiled in the form of ‘Certificate of Analysis’(CoA), should be approved by an authorized representative. The test results should be reported accurately, clearly, unambiguously and objectively, and include all the information necessary for the interpretation of the test results, method used and sections applicable as per regulatory requirements.
Rectification of Errors / Handling of Missed Entries :
DON’T’s:

Entries in documents / records should not be cancelled, erased, obliterated or otherwise rendered illegible ,by using correction fluid/tape, overwriting, crossing out with multiple strokes, etc.
DO’s:

When a correction is necessary, the erroneous entry should be crossed out with a single horizontal line. Enter the correct information as close as possible to original entry that does not obscure the original entry. A brief reason for the correction must be noted as to why the change was made and the correction should be signed and dated. If sufficient space is not available to put the remark, then an annotation mark may be put near the incorrect entry and the annotation mark should be explained on the same page along with signature & date.
 While stamping on documents for effective date or during review retrospectively, if it is discovered that an incorrect stamp has been used, the scenario should be handled in proper way. The error should be corrected by putting correct stamp imprint adjacent to the incorrect one. The incorrect stamp imprint should be struck off by ‘Doer’ with single horizontal line in a manner that it should be readable and not obscured. The ‘Doer’ should sign with date near the struck off, incorrect stamp imprint; this activity should be verified and signed (with date) by reviewer.
Types of Other GMP Documents :
 Good data and records management practices are required to establish, implement and maintain an appropriate quality management system, the details of which should be documented in a format, such as a quality manual. The quality manual, or equivalent documentation, should include a quality policy statement of management’s commitment to an effective quality management system and to good professional practice. These policies should include a code of ethics and code of proper conduct to assure the reliability and completeness of data.
 All equipments related to manufacturing, testing, and packing of pharmaceutical products, APIs, finish products should be maintained and qualified for its intended use.
 Activities such as equipment qualification, analytical method validation, cleaning validation, stability study manufacturing process validation, analytical method or manufacturing technology transfers etc. should be executed on the basis of predefined , preapproved protocols and results of these activities should be documented in a final report with conclusions.
 Standard operating and test procedures should be clear and concise to provide directions to trained personnel regarding a given set of activities.
 A policy for retention and archiving of all records should be established. The length of time depends on the regulatory requirements or company policies consistent with its contractual obligations; however it should be 1 year after the batch expiration date.

Guideline :

Health Products and Food Branch Inspectorate  Cleaning Validation Guideline-   Health Canada.

Definition:

Cleaning Validation:

Cleaning validation is documented evidence that an approved cleaning procedure will provide equipment which is suitable for processing medicinal products.

Types of contaminants

• Chemical – Residues of the previous product
• Biological – Microorganisms
• Physical    – Particulate matter

Solubility of API shall be mentioned as per following Table:

Solubility	Approximate volume of solvent in milliliters per gram of solute
Very soluble	Less than 1 part (< 1)
Freely soluble	From 1 to 10 parts (1 : 10)
Soluble	From 10 to 30 parts (10 : 30)
Sparingly soluble	From 30 to 100 parts (30 : 100)
Slightly soluble	From 100 to 1000 parts (100 : 1000)
Very slightly soluble	From 1000 to 10000 parts (1000 : 10000)
Practically insoluble	More than 10000 parts (> 10000)

LD50 of API shall be mentioned as per following Table:

Probable oral Lethal dose for humans (Mg/ kg)	Included descriptive terms
>15000	Practically non toxic
5000-15000	Slightly toxic
500-5000	Moderately toxic
50-500	Very toxic
5-50	Extremely toxic
<5	Super toxic

Cleanability of API shall be mentioned as per following Table:

Solubility	Approximate volume of solvent in milliliters per gram of solute	Cleanability Index
Very soluble	Less than 1 part (< 1)	Easily cleanable
Freely soluble	From 1 to 10 parts (1 : 10)	Easily cleanable
Soluble	From 10 to 30 parts (10 : 30)	Easily cleanable
Sparingly soluble	From 30 to 100 parts (30 : 100)	Hard to clean
Slightly soluble	From 100 to 1000 parts (100 : 1000)	Hard to clean
Very slightly soluble	From 1000 to 10000 parts (1000 : 10000)	Mechanical water forced required
Practically insoluble	More than 10000 parts (> 10000)	Mechanical water forced required

All equipments parts shall be identified as per rational criteria and categories as per bellow

• Hard to clean
• Direct contact with product
• No direct contact with product

Sampling Techniques :

Visual Inspection (Method For Validation of Cleaning of Equipments):

After cleaning of the equipment visual inspection shall be done using a torch held inclined to the  surface being inspected, and a mirror (attached to stainless steel rod) to inspect the surface of  equipment. Visual inspection shall be done by unaided naked eye.

For visual cleaning;

Verify the cleanliness of the product contact surfaces. Verify the cleanliness of hard to clean areas.

Verify all the product contact dismantled parts before and after assembling.

Surface Swab Sampling:

The direct Sampling technique is also commonly referred to as “Direct Surface Sampling” method.   This is done by Swabbing Technique using Swabs. The direct surface sampling method is the preferred technique.

Sampling Procedure:

Surface sampling is identified as a sampling method considering the design, size and number of equipment.

After the completion of equipment cleaning, visual inspection shall be done.

In case, the surface of equipment is difficult to inspect, a mirror attached to a stick shall be used to inspect the cleanliness of equipment.

Complete product contact surface area shall be sampled for critical hard to clean area/ critical accessories like spray gun, punch, dies, and butter fly valve etc.

Swab Sampling for Chemical analysis:

After visual inspection is found satisfactory swab sampling shall be carried out. Wear hand gloves and nose mask before commencing swab sampling.

The swab must be wetted in purified water or suitable diluents.

Swab area shall be measured with the help of template for swabbing and  the area must be 5cm x 5cm  or as per protocol.

Swabbing shall be done by parallel horizontal and then tilt the swab and do vertical strokes  as  described below to assure that the entire area is swabbed.

After swabbing, place the swab into a stoppered test tube, wrap with aluminum foil and label the test tube for identification of swab sample.

Swab samples must be collected from different areas of equipment as stated in the cleaning validation protocol.

Send the stoppered test tube with swab to Quality Control Laboratory for analysis.

Swab sampling for Microbial analysis:

Wear sterile hand gloves and nose mask before commencing swab sampling to avoid the microbiological contamination. Sterile cotton swab shall be used for swabbing.

The sterile cotton swab shall be soaked in sterile saline.

Swabbing shall be done by parallel horizontal and then tilt the swab and do vertical  strokes  as  described below to assure that the entire area is swabbed.

Swab area shall be measured for swabbing and the area must be 5cm x 6cm.

Microbial swab sample shall be collected before chemical swab.

Swabbing shall be done on the surface of equipments and the area is different from the area of swab taken for chemical analysis.

After swabbing, place the swab into a sterilized stoppered test tube and label the test tube for identification of swab sample.

Swab samples must be collected from different areas of equipment as stated in the cleaning validation protocol.

Send the sterile stoppered test tube with swab to Quality Control – Microbiology Laboratory for analysis.

Rinse Sampling Procedure:

After visual inspection is found satisfactory, the equipment shall be rinsed with the volume of rinsing solvent (purified water) as described in respective cleaning validation protocol (rinse sample shall be performed whenever necessary).

Rinse sample shall be collected in the bottles used for the collection of routine purified water samples.

After the collection of rinse sample, (stopper) close the bottle and label it for identification of rinse sample. Send the rinse sample bottle to Quality Control Laboratory for analysis.

Product Container Lid for Example

Method of analysis:

Methods of analysis used for determination of possible contaminant residues must be specific and sensitive.

The selection of analytical methods shall be validated for at least below  mentioned parameters based  on at least the following but not limited to;

• Precision,
• Specificity
• Linearity and Range,
• Limit of Detection,
• Limit of Quantification,
• Stability of solutions,
• Recovery from Equipment Surface.

FOR WORST CASE APPROACH;

10 PPM Criteria:

MACO =[Mac10] x [Swab Area]/[Shared equipment surface area between products]

Where,

Mac10     = 10 ppm x Minimum Batch Size of Product ‘B’ in kg.

Dose Criteria :

ACCEPTABILITY LIMITS:

Visual inspection criteria:

No quantity of residue should be visible to naked eyes on the equipment after cleaning procedures are performed (i.e. less than 100 mcg /25 cm²).

10ppm criteria: Not more than 10ppm of active pharmaceutical ingredient of previous product is permitted in next product.

Dose based criteria:

Not more than 1/1000 of minimum daily therapeutic dose of  the  previous  product in the maximum daily dose of the next product The acceptability limits for microbiological sample shall be determined based on;

Parameters	Limit Dirty Equipment Surfaces	Limit Cleaned Equipment Surfaces
Total Aerobic Microbial Count (TAMC)	NMT 1000 cfu/swab	NMT 100 cfu/ swab
Total    Combined    Yeasts    and Molds Count (TYMC)	Less Than 10 cfu/swab	Less Than 10 cfu/ swab

Re-validation:

Re-validation shall be performed in case of any change, (at least the following but not limited to)

• Introduction of a new facility, equipment, process or product.
• Change in cleaning procedure.
• Change in cleaning agent used for cleaning.
• Reduction in minimum batch size and lowest dose of the product i.e change in  MACO  limit.
• Major Modification in processing equipment.
• Periodic revalidation after every three years.
• Change in regulatory requirements.

Dirty Equipment Hold Time (DEHT) –

The time from the end of manufacturing till the beginning of

the cleaning process of equipment (also called things like “soiled hold time”)

The Hold Time Study of Dirty Equipments shall be carried out by keeping equipment in idle for a  period of 24 hours in dirty condition. (The Maximum possible hold period under normal conditions) to evaluate microbial contamination on equipment surface and effectiveness of cleaning process.

Clean Equipment Hold Time (CEHT) –

The time from the end of equipment cleaning till subsequent use of equipment (subsequent use includes product manufacturing).

The Hold Time Study of Clean Equipments shall be carried out after completion of  “Type  B  Cleaning”, visual inspection by keeping equipment in idle clean condition up to 72 hours to establish  the expiry of cleaning in view of microbiology.

After the equipments surfaces are found visually clean, sampling and testing shall be carried out for Microbiological enumeration Tests and residual determination (chemical analysis) on the cleaned equipment surfaces at 0 hour interval, then sampling and testing shall be carried out only for Microbiological enumeration Tests at rest intervals as per the sampling plan. (i.e., after 24 hours, 48 hours and 72 hours).

Dirty Equipment Hold Time Period      : 24 Hours

Cleaned Equipment Hold Time Period : 48  Hours

Definition :

What is stability studies

The ability of a pharmaceutical product to retain its physical and chemical properties within specified limits throughout its shelf life.

Types of Stability Studies :

Long term testing

Stability studies under the recommended storage condition for the re-test period or shelf life proposed (or approved) for labeling.

Intermediate testing

Studies conducted at 30°C/65% RH and designed to moderately increase the rate of chemical degradation or physical changes for a drug substance or drug product intended to be stored long term at 25°C.

Accelerated testing

Studies designed to increase the rate of chemical degradation or physical change of a drug substance or drug product by using exaggerated storage conditions as part of the formal stability studies. Data from these studies, in addition to long term stability studies, can be used to assess longer term chemical   effects at non-accelerated conditions and to evaluate the effect of short term excursions outside the label storage conditions such as might occur during shipping. Results from accelerated testing studies are not always predictive of physical changes.

Climatic zones The four zones in the world that are distinguished by their characteristic prevalent annual climatic conditions.

Climatic Zone No.	Definition	Storage Condition	Areas covered under the zone
I	Temperate climate	21°C & 45% RH.	United     Kingdom,      Northern                Europe, Canada, Russia, United states, Japan etc.
II	Subtropical and Mediterranean climate	25°C/60% RH	United   States,   Japan,  Southern Europe (Portugal-Greece) etc.
III	Hot & dry climate	30°C/35% RH	Australia, Argentina, Egypt, Iran, Iraq, Sudan, India etc.
IVA	Hot & humid climate	30°C/65%	Brazil,     Ghana,     Indonesia,               Nicaragua, Srilanka, Vietnam, Philippines, Uganda, Thailand, India etc.
IVB	Hot & very humid climate	30°C/75%	Brazil, Asian countries etc.

Factors affecting stability of the product

Temperature:

The rate of chemical reaction increases exponentially for each 10°C increase in temperature. This relationship has been observed for nearly all drug hydrolysis and some drug oxidation reaction.

Light:

Exposure to primarily, UV illumination may cause oxidation (photo oxidation) and scission (Photolysis) of covalent bonds.

Air:

Presence of oxygen, nitrogen.

Humidity (Moisture):

Esters & beta-lactoms are the chemical bonds that are most likely to hydrolyze in the presence of water.

E.g. the acetyl ester in aspirin is hydrolyzed to acetic acid and salicylic acid in the presence of moisture, but in a dry environment the hydrolysis of aspirin is negligible.

Selection of Batches

For new drug product, samples of at least three consecutive validation batches shall be kept for accelerated, Intermediate and long-term stability.

For routine stability study, one commercial batch shall be kept for long term stability on every year.

Testing frequency

Testing frequency shall be determined based on condition at which stability is performed.

Accelerated

Accelerated stability shall be conducted at 0, 3 and 6 months.

Long term

Long-term stability studies shall be carried out at the intervals of, Every three months on first year 0, 3, 6,9,12,

Every six months on second year 12, 18, 24

Every year thereafter through the proposed shelf life 24, 36, 48 and 60

Eg: 0, 3,6,9,12,18,24,36,48 and 60 months.

Intermediate Intermediate stability studies (minimum four time points, including initial and final points) shall be carried out at 0,3,6,9 and 12 months or up to 60 months.

Sampling for Stability Study

QA shall inform to QC regarding type of stability study to be performed. QC shall calculate the sample quantity and shall inform to QA.

Total sample quantity per batch shall be equivalent to 1.5 times of the quantity required for single complete or partial analysis & based on number of stations plus additional one station (since stability testing has to be continued for 12 month beyond the expiry).

Incubation of Stability Samples and Storage conditions

Samples shall be incubated as per below guideline.

Identify the storage conditions based on the Pharmacopoeial data or literature information or R&D information. For add on batch use long term storage conditions.

The long term testing shall cover a minimum of 12 months’ duration on at least three validation batches at the time of submission and shall be continued for a period of time sufficient to cover the proposed shelf life.

Long term, accelerated, and, where appropriate, intermediate storage conditions for drug products are detailed in the sections below.

Study	Storage condition	Minimum time period covered by data at submission
Long term	25°C ± 2°C / 60% RH ± 5% RH or 30°C ± 2°C / 65% RH ± 5% RH	12 months
Intermediate*	30°C ± 2°C / 65% RH ± 5% RH	6 months
Accelerated	40°C ± 2°C / 75% RH ± 5% RH	6 months

* If 30°C ± 2°C / 65% RH ± 5% RH is the long-term condition, there is no intermediate condition.

If long-term studies are conducted at 25°C ± 2°C/60% RH ± 5% RH and “significant change” occurs at any time during 6 months’ testing at the accelerated storage condition, additional testing at the intermediate storage condition should be conducted and evaluated against significant change criteria.

The initial application should include a minimum of 6 months’ data from a 12-month study at the intermediate storage condition. Temperature & Humidity of stability incubator shall be monitored on daily basis. If incubation of the stability samples is delayed by 30 days or more from the release date of the batch, initial (0 month) analysis shall be performed again before incubation.

Analysis of the sample shall be performed on the due date or if not possible, then  complete within  below tolerance limit from due date.

Sr. No.	Stability Station	Tolerance (From due date of analysis)
1.	1M , 2M, 3M Accelerated, 3M long term, 3M Intermediate term	± 07 days
2.	6M Accelerated 6M, 9M, 12M long term. 6M, 9M, 12M Intermediate term.	± 15 days
3.	18M & onwards of long term.	± 30 days

If there is any out of trend result or failure to meet specification (significant change)  in  stability analysis, results shall be intimated to Head – QC.

Head – QC or designee shall investigate the out of trend (OOT) results according to the OOT SOP .

In case of Changes in the manufacturing process or site:

If minor changes done in the manufacturing process, Sample from batches produced under each change shall be added to stability program (one batch).

If major changes done in the manufacturing process, collect the samples from the new batches (three batches) and perform the stability like new product. In such a case the protocol and report procedure number shall be changed.

In case of manufacturing site change, evaluate the affect on stability of the drug product by keeping one batch for stability.

Stability guideline :

ICH guideline: ICH Q1A (R2)

Orange guide

DEFINATION:

New Vendor: Manufacturer identified by Formulation Development or purchase department as a manufacturer to supply of a specific material from a specific manufacturing site.

Approved Vendor: Manufacturer of raw material, primary and printed packaging material, which has been approved by QA to supply a specific material from specific site, based on the satisfactory cGMP history as well as compliance of material to specification.

PROCEDURE:

VENDOR DEVELOPMENT

The requirement of new raw & packing materials and their profiles shall be given by the formulations development department.

In charge-purchase (Vendor development) shall identify the vendors with the available  information based on specifications provided by formulations development department.

ASSESSMENT OF NEW VENDOR ( S) FOR NEW / EXISTING MATERIAL :

TEMPORARY APPROVED VENDORS

In order to select a new vendor, evaluation of the manufacturer’s capability, service performance and quality history is required. Purchase department shall collect and maintain information of the new  vendor through the vendor registration form for manufacturer and for supplier or Trade.

Purchase department will get technical information regarding the material through vendor questionnaire from the vendor which includes the brief manufacturing process, TSE/BSE free declaration, impurity profile, residual solvent information, GMO free declaration, Melamine free declaration, Gluten free declaration and stability data/shelf life statement etc. as applicable depending upon the type of material.

GMO : Genetically Modified Organism

Note: For non-critical excipients requirement of impurity profile, residual solvent information, stability data, GMO/Melamine/Gluten free declarations are not mandatory.

Purchase department shall ask the vendor for analytical method and analytical method  validation data for the materials claiming residual solvents. Based on the evaluation of above information and vendor registration form, Purchase/Formulation development department shall ensure that vendor is ready to supply material of required grade with specific requirement, if any.

Purchase department shall ask the vendor for pre-purchase samples of at least one batch depending    upon the along with its certificate of analysis and shall be sent to Formulation Development and/or Quality Control for analysis.

Formulation Development and/or Quality Control shall evaluate the source material lots and on compliance of the sample as per specification and shall confirm the suitability as per specification to purchase department.

Formulation Development and/Quality Control will intimate the purchase and QA for suitability of sample.

Based on the assessment report from Formulation Development and/Quality Control satisfactory evaluation of data provided by the vendor, the new vendor shall be considered as a ‘Temporary Approved’.

The vendor list contains Material Code, Material Name, Synonym/ Storage Condition, Manufacturer Name and Site Address, Suppliers Name and Address and current approval status. The vendor list shall be prepared, reviewed and approved. A separate vendor list shall be prepared for US/UK market and others.

Once vendor is temporary approved, vendor code is to be assigned to the particular vendor as well as material code in SAP is to be generated by purchase department in co-ordination with SAP department.

APPROVED VENDORS

Temporary approved” vendor becomes “Approved” vendor if following conditions are met-

For Manufacturer

Another Two commercial lots supplied by Temporary approved vendors are analysed and passed.

In case of API/ Primary packing material, vendor questionnaire is filled and vendor audit is done and complied.

In case of excipients and secondary packing material questionnaire is  completed.(if required, audit to   be carried out)

When manufacturing site audit is required, it shall be carried out by site QA/CQA to assess compliance with cGMP requirements.

The manufacturing site of the vendor shall be audited as per the checklist.

Based on the audit findings, a detailed report shall be classified as critical(C), Major (M) and minor (N) as described under definitions.

The purchase department shall send the site audit report prepared by site QA/CQA to the vendor. The vendor should respond in a period of 30 days after receipt of the audit report from purchase department.

The audit compliance report received from the new vendor shall be evaluated by the audit team members and recommendations shall be given to approve or reject the vendor by head QA.

Re-audit may be required for ensuring compliance in case of critical deficiencies observed during the audit.

QA shall update the vendor list once in 6 months to include or exclude approved vendor and to reflect the change in the status of vendors.

PERIODIC EVALUATION OF APPROVED VENDORS :

For approved vendor’s evaluation, following steps shall be followed:

Evaluation of the vendor’s quality performance shall be done once in a year. This annual evaluation

shall include review of rejection rate of the vendor’s lots and resolution of quality issues, if any

Yearly trending of all API from the Vendor shall be carried out of quality issues, if any.

Reassessment of quality systems shall be carried out if the rejection rate on quality grounds is higher than 20%.

All the vendor’s of API and primary packing materials shall be audited once in three years.

The vendor should respond with audit compliance report in a period of 30 days after receiving the audit report from purchase department.

If the compliance is not satisfactory, then the vendor rating will be downgraded or disapproved and deleted from the list. QA will update the vendor list accordingly and communication of the same shall  be sent to QC, warehouse and purchase department.

DISQUALIFICATION OF VENDORS :

Vendors failing to meet the GMP requirements and those consistently (up to three lots) failing to meet quality standards shall be disqualified and blocked for supply of material by QA. However vendor can immediately be disqualified, Incase of any critical failure e.g. failing in potency (Assay below 80 %), microbial test (failure in pathogens). If the satisfactory corrective actions are taken by the vendor to resolve the quality problems and non- compliances, the vendor shall be re-approved for the supply.

FLOW CHART OF VENDOR APPROVAL

What is Quality Management system :

A Quality management system (QMS) is the core of any quality and compliance process. It is a regulatory requirement that the Food and Drug Administration (FDA) and other global regulatory bodies consider critical. An automated QMS system reduces audit time and findings and lowers the risk of product recalls. It improves product quality and safety, increases customer satisfaction and ensures FDA and ISO compliance.

Pharmaceutical Quality professionals are facing more challenges, and have more opportunities to improve quality and compliance than ever before. Mergers and acquisitions, complex supply chains, data integrity issues, and tightening regulations are all forces that affect pharmaceutical quality strategies and processes on a day-to-day basis. Plus, the FDA and other regulatory bodies are increasingly focused not only on compliance, but on the importance of building a culture of Quality management in the pharmaceutical industry.

An effective pharmaceutical Quality management system (QMS) will help you develop a culture of quality, support data integrity, keep suppliers under control, and maintain overall compliance. QMS data must also be structured to drive consistent metrics, risk calculations, and other trend analysis.

What is the Purpose of Quality Management system :

AQ management system can be defined as a collection of business processes that are focused on meeting customer requirements on a consistent basis. This may seem simple enough, however, it is essential that certain obstacles are overcome for your QMS to be successful.

With this in mind, ask yourself the following questions:

• Do the same mistakes keep on being repeated?
• Is there lack of visibility between each of your departments?
• Do you have a high customer churn rate, negative customer reviews or perhaps a declining bottom line?

If you answered yes to any of the above, it may be that your QMS is not working as it should be.

The purpose of a quality management system is to ensure every time a process is performed, the same information, methods, skills and controls are used and applied in a consistent manner. If there are process issues or opportunities, this is then fed into the quality management system to ensure continuous improvement.

Importance of Quality Management System:

Here are reasons why quality management systems are so important for pharmaceutical companies:

Lessen the Risk of Errors :

The most obvious reason to invest in a QMS is to assist your company to reduce errors made when producing products. Without an advanced system where all employees involved understand their roles and responsibilities and communicate with each other, there will be more chance that errors will be made. Pharmaceutical companies of all sizes are at risk of doing mistakes without QMS in place. With an advanced QMS in place, everyone understands the tasks they need while completing a project. And, what steps ought to be taken each time to lessen the risk of errors from occurring.

Cut Costs with Quality Management System :

Errors can result in the wastage of products and money for your company. Not only are you wasting money on scraping products with errors that don’t meet the standards they require, but also you are wasting your employee’s time. Redo the work because of errors takes time far from other important tasks that still ought to be complete. As an advanced QMS, it streamlines production, makes it more efficient, and helps everyone involved become more productive. Also, companies may be able to see an increase in profits as well.

Encourage you to Constantly Upgrade :

Implementing an advanced QMS is a great place to begin, but the work doesn’t end there. The current system which you are using is unlikely to remain consistent, which is really a good thing. A quality management system encourages companies to keep them updated to improve their operations and makes it easier to identify areas where you ought to change. Technologies may also change, requiring you to adapt and upgrade your system to run more smoothly.

Customer Satisfaction :

Improving your company’s efficiency and production process are huge benefits to having an advanced QMS in place. However, the foremost important goal of all pharmaceutical companies is to make products that will help customers to live better. Ensuring that you’re producing high-quality products that are thoroughly checked over throughout the whole production process means you’re delivering better products to your customers. Customer satisfaction is more important for the companies, as they give your company positive reviews, which leads to increase sales.