Master Batch Record

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Subpart F Production and Process Controls

    § 211.100 - Written procedures; deviations
   § 211.101 - Charge-in of components
   § 211.103 - Calculation of yield
   § 211.105 - Equipment identification
   § 211.110 - Sampling and testing of in-process materials and
drug products
   § 211.111 - Time limitations on production
   § 211.113 - Control of microbiological contamination
   § 211.115 - Reprocessing

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Production and Process Controls

  • Premise: If you make a drug the same way every time, its quality will always be on spec.
  • Purpose: To build quality into the drug throughout the production process.

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Subpart J Records and Reports

    § 211.180 - General requirements
   § 211.182 - Equipment cleaning and use log
   § 211.184 - Component, drug product container, closure, and

labeling records
   § 211.186 - Master production and control records
   § 211.188 - Batch production and control records
   § 211.192 - Production record review
   § 211.194 - Laboratory records
   § 211.196 - Distribution records
   § 211.198 - Complaint files

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Records and Reports

  • Premise: If it’s not documented, it didn’t happen.
  • Purpose: To provide a paper trail for reviewers (internal and external) showing all the information necessary to make/substantiate decisions.

  • All records are to be retained (and available for review by an investigator) until at least 1 year after the expiration date of the batch of drug to which it applies.

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Master Batch Records - Contents

All the information a trained operator needs

to make the product the same way every time.

Typical MBR Contents:

  • Cover Page, incl. Product Name, Dosage Form
  • Process Flow Diagram or Written Overview
  • Components List, incl. Quantity/Quality
  • Equipment Specifications
  • Detailed Procedural Steps and Control Instructions
  • Yield Estimate
  • Disposition Section

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Master Batch Records

MBRs – Think of them as recipes, very elaborate recipes.

Here’s a famous recipe

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Master Batch Records

MBRs – Think of them as recipes, very elaborate recipes.

Here’s a famous recipe

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Typical MBR Contents:

Cover Page, incl. Product Name, Dosage Form

Process Flow Diagram or Written Overview

Components List, incl. Quantity/Quality

Equipment Specifications

Detailed Procedural Steps and Control Instructions

Yield Estimate

Disposition Section

*

Typical MBR Contents:

Cover Page, incl. Product Name, Dosage Form

Process Flow Diagram or Written Overview

Components List, incl. Quantity/Quality

Equipment Specification

Detailed Procedural Steps and Control Instructions

Yield Estimate

Disposition Section

*

Typical MBR Contents:

Cover Page, incl. Product Name, Dosage Form

Process Flow Diagram or Written Overview

Components List, incl. Quantity/Quality

Equipment Specifications

Detailed Procedural Steps and Control Instructions

Yield Estimate

Disposition Section

*

Typical MBR Contents:

Cover Page, incl. Product Name, Dosage Form

Process Flow Diagram or Written Overview

Components List, incl. Quantity/Quality

Equipment Specifications

Detailed Procedural Steps and Control Instructions

Yield Estimate

Disposition Section

*

Typical MBR Contents:

Cover Page, incl. Product Name, Dosage Form

Process Flow Diagram or Written Overview

Components List, incl. Quantity/Quality

Equipment Specifications

Detailed Procedural Steps and Control Instructions

Yield Estimate

Disposition Section

*

Typical MBR Contents:

Cover Page, incl. Product Name, Dosage Form

Process Flow Diagram or Written Overview

Components List, incl. Quantity/Quality

Equipment Specifications

Detailed Procedural Steps and Control Instructions

Yield Estimate

Disposition Section

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Executed Batch Records

Sufficient documentation to demonstrate that the batch was made according to the approved procedure

  • Accurate reproduction of master
  • Steps completed, blanks filled in, signed, dated
  • Label control documentation
  • Description of drug product containers / closures used
  • Any investigations performed

  • Reviewed by QA

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Batch Records – Cover Page

23Jan2008

1/21/08

23Jan08

1/21/08

Name & strength of the product

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Novelle Pharmaceuticals, Inc.
Batch Record for the Formulation of

Newdrug® 50mg Dimethylchickenwire Coated Tablets

Product Number: NPI-034

Stock Number: 28092

Nominal Batch Size: 1,200,000 tablets

Lot Number: ____________

Effective Date:

Version: 2

Written / Revised By: __________________ Date: __________ Issue Date: __________

Technical Reviewer: __________________ Date: __________ Issued By: __________

QA Appproval: __________________ Date: __________ Production Start Date: __________

Batch Records – Cover Page

23Jan2008

1/21/08

23Jan08

1/21/08

Name and amount of each active ingredient per dosage unit

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Novelle Pharmaceuticals, Inc.
Batch Record for the Formulation of

Newdrug® 50mg Dimethylchickenwire Coated Tablets

Product Number: NPI-034

Stock Number: 28092

Nominal Batch Size: 1,200,000 tablets

Lot Number: ____________

Effective Date:

Version: 2

Written / Revised By: __________________ Date: __________ Issue Date: __________

Technical Reviewer: __________________ Date: __________ Issued By: __________

QA Appproval: __________________ Date: __________ Production Start Date: __________

Batch Records – Cover Page

23Jan2008

1/21/08

23Jan08

1/21/08

Description of dosage form (tablet, capsule, liquid,

suspension…)

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Novelle Pharmaceuticals, Inc.
Batch Record for the Formulation of

Newdrug® 50mg Dimethylchickenwire Coated Tablets

Product Number: NPI-034

Stock Number: 28092

Nominal Batch Size: 1,200,000 tablets

Lot Number: ____________

Effective Date:

Version: 2

Written / Revised By: __________________ Date: __________ Issue Date: __________

Technical Reviewer: __________________ Date: __________ Issued By: __________

QA Appproval: __________________ Date: __________ Production Start Date: __________

Batch Records – Cover Page

23Jan2008

1/21/08

23Jan08

1/21/08

Prepared by one person,

Checked by another

Approved by Quality Unit

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Novelle Pharmaceuticals, Inc.
Batch Record for the Formulation of

Newdrug® 50mg Dimethylchickenwire Coated Tablets

Product Number: NPI-034

Stock Number: 28092

Nominal Batch Size: 1,200,000 tablets

Lot Number: ____________

Effective Date:

Version: 2

Written / Revised By: __________________ Date: __________ Issue Date: __________

Technical Reviewer: __________________ Date: __________ Issued By: __________

QA Appproval: __________________ Date: __________ Production Start Date: __________

Components List

An MBR must contain a complete list of components and amounts to be used and a statement re. any calculated overages

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NOVELLE PHARMA

NEWDRUG 50

PF07-34

DIMETHYLCHICKENWIRE 50 MG

BLISTER PACK FILM

*

NOVELLE PHARMA

NEWDRUG 50

PF07-34

DIMETHYLCHICKENWIRE 50 MG

BLISTER PACK FILM

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NOVELLE PHARMA

NEWDRUG 50

PF07-34

DIMETHYLCHICKENWIRE 50 MG

BLISTER PACK FILM

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Dispensing

Dispensing of the components that are to be used in the upcoming batch is common practice. Dispensed ingredients must be properly labeled.

Dispensed for:

Product: Toll House Cookies

Lot No. B08- 13

Component: Cake Flour Gross Wt.: 44.8 kg

Stock No.: 34988 Tare Wt. 4.8 kg

Lot No: 34M572-A Net Wt.: 40.0 kg

Weighed by: _________ Date: ______

Checked by: _________ Date: ______

M J C

10 Feb 08

J K F

10 Feb 08

Dispensed components are usually staged in a specific area organized by production batch

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Dispensing –
Like having a Sous Chef help out

Dispensed for:

Product: Toll House Cookies

Lot No. B08- 13

Component: Cake Flour Gross Wt.: 44.8 kg

Stock No.: 34988 Tare Wt. 4.8 kg

Lot No: 34M572-A Net Wt.: 40.0 kg

Weighed by: _________ Date: ______

Checked by: _________ Date: ______

Flour lot no

Batch identity

weighed by

Flour lot no

Batch identity

weighed by

Flour lot no

Batch identity

weighed by

M J C

10 Feb 08

J K F

10 Feb 08

REJECTED

Product: NPI-034

Batch Number: 0208B

REJECTED

Product: NPI-034

Batch Number: 0208B

REJECTED

Product: NPI-034

Batch Number: 0208B

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Batch Record Procedural Steps

Written production and process control procedures shall be followed and shall be documented at the time of performance

23Jan2008

13:42

13:57

15 min

T S P

12 F e b 08 13:57

B08-13

*

Novelle Pharmaceuticals, Inc.
Master Batch Record for the Formulation of Newdrug® 50mg Coated Tablets

LOT NUMBER: ___________

EFFECTIVE DATE: __________

STOCK NUMBER: 28092

REVISION NUMBER: 2

PRODUCT NUMBER: NPI-034

Page 17 of 42

Step

Action

Initials

Date / Time

23

Close the hatch on Blender EQ17B and blend the mixture for 14 minutes ± 2 minutes.

Start Time: __________

End Time: __________

Total Blend Time: __________

_________

_______________

Batch Record Procedural Steps

Each component shall be added to the batch by one person
and verified by a second person.

23Jan2008

B08-13

*

Novelle Pharmaceuticals, Inc.
Batch Record for the Formulation of Newdrug® 50mg Dimethylchickenwire Coated Tablets

LOT NUMBER: ___________

EFFECTIVE DATE: __________

STOCK NUMBER: 28092

REVISION NUMBER: 2

PRODUCT NUMBER: NPI-034

Page 16 of 42

Step

Action

Initials

Date / Time

22

Charge 60.00 kg of dimethylchickenwire, stock number 2463, into blender EQ17B.

Gross Weight: _______ kg Stock Number: ________

Tare Weight: _______ kg Lot Number: ________

Net Weight: _______kg

__________

__________

________________

________________

In-Process Control Tests & Specifications
- Check-points along the path to the final product

IPC Test examples:

  • Test for water content after a drying operation to ensure that the product is sufficiently dry to proceed to the next step.
  • Check for homogeneity in a blend to ensure that the active ingredient is evenly distributed throughout the batch.
  • Check the alcohol content of a batch of pale ale before bottling

Specification:

“Valid in-process specifications shall be consistent with drug product final specifications and shall be derived from previous acceptable process average and process variability estimates where possible.”

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In-Process Control Tests & Specifications
- Check-points along the path to the final product

IPC Test examples:

  • Test for water content after a drying operation to ensure that the product is sufficiently dry to proceed to the next step.
  • Check for homogeneity in a blend to ensure that the active ingredient is evenly distributed throughout the batch.
  • Check the alcohol content of a batch of pale ale before bottling

Specification:

“Valid in-process specifications shall be consistent with drug product final specifications and shall be derived from previous acceptable process average and process variability estimates where possible.”

*

In-Process Control Tests & Specifications
- Check-points along the path to the final product

IPC Test examples:

  • Test for water content after a drying operation to ensure that the product is sufficiently dry to proceed to the next step.
  • Check for homogeneity in a blend to ensure that the active ingredient is evenly distributed throughout the batch.
  • Check the alcohol content of a batch of pale ale before bottling

Specification:

“Valid in-process specifications shall be consistent with drug product final specifications and shall be derived from previous acceptable process average and process variability estimates where possible.”

*

In-Process Control Tests & Specifications
- Check-points along the path to the final product

IPC Test examples:

  • Test for water content after a drying operation to ensure that the product is sufficiently dry to proceed to the next step.
  • Check for homogeneity in a blend to ensure that the active ingredient is evenly distributed throughout the batch.
  • Check the alcohol content of a batch of pale ale before bottling

Specification:

“Valid in-process specifications shall be consistent with drug product final specifications and shall be derived from previous acceptable process average and process variability estimates where possible.”

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Homogeneity Testing in a V-Blender

Samples of the blended solids must be taken from established locations within the blender according to a plan such as the one depicted below.

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Sample Thief

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Statistical Sampling

In packaging operations, to provide assurance that each package in the entire lot meets specifications, a pre-determined number of packages are examined at given time intervals throughout the packaging run for defects.

The type of defects that are categorized as minor, major, or critical are defined by the packager.

The total number of defects must be less than the limit as defined by ANSI/AQL Z1.4 (or similar system).

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Minor, Major, or Critical Defect?

Crooked label

Missing package insert

Wrong Lot number

Low tablet count

Wrong tablets

Too many tablets per blister compartment

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Minor, Major, or Critical Defect?

Crooked label

Missing package insert

Wrong Lot number

Low tablet count

Wrong tablets

Too many tablets per blister compartment

m

*

Minor, Major, or Critical Defect?

Crooked label

Missing package insert

Wrong Lot number

Low tablet count

Wrong tablets

Too many tablets per blister compartment

m

M

*

Minor, Major, or Critical Defect?

Crooked label

Missing package insert

Wrong Lot number

Low tablet count

Wrong tablets

Too many tablets per blister compartment

m

M

C

*

Minor, Major, or Critical Defect?

Crooked label

Missing package insert

Wrong Lot number

Low tablet count

Wrong tablets

Too many tablets per blister compartment

m

M

C

M

*

Minor, Major, or Critical Defect?

Crooked label

Missing package insert

Wrong Lot number

Low tablet count

Wrong tablets

Too many tablets per blister compartment

m

M

C

M

C

*

Minor, Major, or Critical Defect?

Crooked label

Missing package insert

Wrong Lot number

Low tablet count

Wrong tablets

Too many tablets per blister compartment

m

M

C

M

C

C

*

NEWDRUG 50G

PF07-34

NEWDRUG 50G

NEWDRUG 50G

NOVEllE PHARMA

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In-Process Control Tests and Specifications - Failures

“Rejected in-process materials shall be identified and controlled under a quarantine system designed to prevent their use in manufacturing or processing operations for which they are unsuitable.”

REJECTED

Product: NPI-034 – Uncoated Tablets

Batch Number: 0208B

REJECTED

Product: NPI-034

Batch Number: 0208B

Flour lot no

Batch identity

weighed by

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Calculation of Yields

112 kg

150 kg

150 kg

112 kg

156 kg

A Master Batch Record must include:

  • The theoretical quantities expected at appropriate phases of processing

  • The theoretical yield and expected yield range

An Executed Batch Record must include the actual yields

Overall Theoretical Yield: 156.0 kg (1,200,000 tablets)

Expected Yield: 137.3 – 148.2 kg

(1,068,000 – 1,140,000 tablets)

89 – 95%

Actual Yield: 140.1 kg = 91%

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Higher than Expected Yield

Not necessarily a good thing.

Scenario: The weight of a batch of material removed from a reactor was

1.2 kg greater than the weight of materials charged.

Investigation:

  • All charges were weighed by one person and witness by another.
  • All plastic bags, flashlights, hatch bolts are accounted for
  • The same scale was used for the charged materials as for the discharged material
  • Analysis of the discharged material indicated the presence of an impurity that was identified as toluene, a material not used in the process.

Root Cause: Another unit in the plant had caused the vent header to pressure up, and allowed condensed toluene to back flow into the reactor.

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Higher than Expected Yield

Not necessarily a good thing.

Scenario: The weight of a batch of material removed from a reactor was 1.2 kg greater than the weight of materials charged.

Investigation:

  • All charges were weighed by one person and witness by another.
  • All plastic bags, flashlights, hatch bolts are accounted for
  • The same scale was used for the charged materials as for the discharged material
  • Analysis of the discharged material indicated the presence of an impurity that was identified as toluene, a material not used in the process.

Root Cause: Another unit in the plant had caused the vent header to pressure up, and allowed condensed toluene to back flow into the reactor.

*

Higher than Expected Yield

Not necessarily a good thing.

Scenario: The weight of a batch of material removed from a reactor was 1.2 kg greater than the weight of materials charged.

Investigation:

  • All charges were weighed by one person and witness by another.
  • All plastic bags, flashlights, hatch bolts were accounted for.
  • The same scale was used for the charged materials as for the discharged material
  • Analysis of the discharged material indicated the presence of an impurity that was identified as toluene, a material not used in the process.

Root Cause: Another unit in the plant had caused the vent header to pressure up, and allowed condensed toluene to back flow into the reactor.

*

Higher than Expected Yield

Not necessarily a good thing.

Scenario: The weight of a batch of material removed from a reactor was 1.2 kg greater than the weight of materials charged.

Investigation:

  • All charges were weighed by one person and witness by another.
  • All plastic bags, flashlights, hatch bolts were accounted for.
  • The same scale was used for the charged materials as for the discharged material. It was within calibration parameters.
  • Analysis of the discharged material indicated the presence of an impurity that was identified as toluene, a material not used in the process.

Root Cause: Another unit in the plant had caused the vent header to pressure up, and allowed condensed toluene to back flow into the reactor.

*

Higher than Expected Yield

Not necessarily a good thing.

Scenario: The weight of a batch of material removed from a reactor was 1.2 kg greater than the weight of materials charged.

Investigation:

  • All charges were weighed by one person and witness by another.
  • All plastic bags, flashlights, hatch bolts were accounted for.
  • The same scale was used for the charged materials as for the discharged material. It was within calibration parameters.
  • Analysis of the discharged material indicated the presence of an impurity that was identified as toluene, a material not used in the process.

Root Cause: Another unit in the plant had caused the vent header to pressure up, and allowed condensed toluene to back flow into the reactor.

*

Higher than Expected Yield

Not necessarily a good thing.

Scenario: The weight of a batch of material removed from a reactor was 1.2 kg greater than the weight of materials charged.

Investigation:

  • All charges were weighed by one person and witness by another.
  • All plastic bags, flashlights, hatch bolts were accounted for.
  • The same scale was used for the charged materials as for the discharged material. It was within calibration parameters.
  • Analysis of the discharged material indicated the presence of an impurity that was identified as toluene, a material not used in the process.

Root Cause: Another unit in the plant had caused the vent header to pressure up, and allowed condensed toluene to backflow into the reactor.

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Deviations

Deviation Investigation Reports are required whenever an action or a result is outside the established limits or expectations.

A DR includes:

  • Description of the deviation
  • Investigation into the root cause
  • Corrective Action to current batch
  • Preventive Action for future batches
  • Evaluation - Effect of the deviation on the current, previous, or subsequent batches.

Deviations are NO FUN !

“CAPA”

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Deviation Description

For example:

The final target temperature of the product during the granulation cooldown step (30±2°C) was not achieved after 16 hours of cooling. Normal cooldown time is approximately 6 hours.

The maximum allowable time for completion of this step is 18 hours.

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Deviation Investigation

  • The inlet air temperature was within the acceptable range of 15 to 25°C throughout the cooling step (see attached temperature chart).
  • While attempting to verify the calibration of the thermocouples, it was noticed that the product thermocouple was coated with a hard layer of solids. This coating was insulating the thermocouple from reading the true temperature of the granulation mixture.

But you can’t stop there –

How did the thermocouple get coated?

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Deviation Investigation

  • The inlet air temperature was within the acceptable range of 15 to 25°C throughout the cooling step (see attached temperature chart).
  • While attempting to verify the calibration of the thermocouples, it was noticed that the product thermocouple was coated with a hard layer of solids. This coating was insulating the thermocouple from reading the true temperature of the granulation mixture.

But you can’t stop there –

How did the thermocouple get coated?

*

Deviation Investigation

  • The inlet air temperature was within the acceptable range of 15 to 25°C throughout the cooling step (see attached temperature chart).
  • While attempting to verify the calibration of the thermocouples, it was noticed that the product thermocouple was coated with a hard layer of solids. This coating was insulating the thermocouple from reading the true temperature of the granulation mixture.

But you can’t stop there –

How did the thermocouple get coated?

*

Deviation Investigation

  • The inlet air temperature was within the acceptable range of 15 to 25°C throughout the cooling step (see attached temperature chart).
  • While attempting to verify the calibration of the thermocouples, it was noticed that the product thermocouple was coated with a hard layer of solids. This coating was insulating the thermocouple from reading the true temperature of the granulation mixture.

  • The equipment file for Granulator EQ-14C shows that a new set of spray nozzles was installed just prior to the current batch. The new nozzles are identical to the ones that were installed previously (Replacement in Kind). The Work Order documenting the installation of the new nozzles does not include documentation of the spacing of the spray nozzles.

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Deviation - Corrective Action

  • The coating around the thermocouple was removed and the cooldown step was restarted.
  • The temperature lined out at 28°C within 30 minutes.
  • The granulation cooldown step was completed.

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Deviation – Preventive Actions

The granulator thermocouple became coated with solids because the new spray nozzles were installed such that the left-most spray nozzle constantly wetted the thermocouple. As solids were fluidized, they stuck to the wet thermocouple and built up an insulating layer.

The Equipment Master File will be updated to specify the acceptable positions of the spray nozzles on the spray arm. The Master Batch Record will be revised to specify that the spacing of the nozzles be checked prior to use.

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Deviation - Evaluation

  • Effect on current batch: None. The final cooldown temperature of 28°C was within the acceptable range of 30±2°C, and the total cooldown time of 16 ½ hours was less than the maximum allowable time of 18 hours.
  • Effect on previous batches: None. The new nozzles were installed just prior to the current batch.
  • Effect on future batches: None. Corrective Action must be performed prior to next batch.

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Laboratory Records

Laboratory records must include complete data derived from all tests necessary to assure compliance with established specifications and standards.

Each Lab Record must include all the information, data, calculations and results of the test.

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Laboratory Records

Novelle Pharma

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Laboratory Records

Novelle Pharma

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Laboratory Records

Novelle Pharma

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Laboratory Records

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Review & Disposition

  • After a batch of drug has been produced, the batch record and all associated documentation is reviewed by the Quality Unit “to determine compliance with all established, approved written procedures”
  • QA may designate the batch as:

  • Alternately, they may quarantine a batch for reprocessing at a later date.

APPROVED

REJECTED

OR

QUARANTINE

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Reprocessing

A product or intermediate may be reprocessed in certain circumstances.

Reprocessing procedure must be written, and executed as written.

Reprocessing must be approved by the Quality Unit.

Examples:

  • Labels are smeared and illegible
  • Purity specification was not met, but laboratory work has shown that recrystallization of the product will remove the impurity to an acceptable level
  • The filter cloth tore during filtration, allowing solids to get into the filtrate

Reprocessing in normally initiated by a Deviation Investigation, otherwise the “reprocessing” steps should be incorporated into the MBR.

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Equipment Identification

Blender EQ17B

Product: NPI-034

Dried, Unmilled Granules - Step 78, Batch B08-13

Equipment ID

Contents ID and

Phase of Mfg

- All major pieces of equipment and process lines are to have unique identifiers.

- The contents of major pieces of equipment which are in use must be identified.

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Equipment Logs

Written records of the cleaning, maintenance and use of major equipment

*

Blender EQ17B Log Sheet

Start Date

Activity

Lot No. /

WO No.

Product

End

Date

Clean/Maint

Disposition

Init / Date*

Init / Date*

1/13/08

Production

A08-12

ColdMed 10 mg

1/18/08

n/a

1/21/08

Partial Clean

A08C-07

n/a

1/22/08

pass

GEJ

1/22/08

EHD

1/22/08

1/23/08

Production

A08-33

ColdMed 25 mg

1/28/08

n/a

1/29/08

Full Clean

B08C-06

n/a

2/1/08

Pass

GEJ

2/1/08

EHD

2/1/08

2/1/08

Replace spray nozzles

WO-1435

n/a

2/3

Complete

MM

2/3/08

EHD

2/3/08

2/4/08

Maint. Clean

B08C-06

n/a

2/6/08

Pass

LSP

2/6/08

KKT

2/6/08

2/11/08

Production

B08-13

NewDrug 50mg

*Required to confirm maintenance and cleaning

Inventory of Components,
Drug Product Containers & Closures, and Labels

Inventory logs are required to provide traceability of Components,
Drug Product Containers & Closures, and Labels:

*

Component name: Microcrystalline Cellulose

Receiving Code: 1782667

Grade: Food Grade

Date of Receipt: Dec 13, 2007

Supplier name: J.T. Baker

Supplier Lot number: MC113D

Manufacturer name: BulkChem Company

Manufacturer Lot number: n/a

Quantity received: 6 x 50kg drums

Disposition: Approved Date: Dec 21, 2007

Container No. __1__ of __6__ Tare wt. (from package label): ___4.86__ kg

Date

Initials

Activity

Batch

Number

Gross (kg)

Tare * (kg)

Net ** (kg)

12/13/07

T J K

Receipt

54.98

4.86

50.12

12/14/07

LT

Remove QC Sample

54.96

4.86

50.10

12/28/07

JED

Removed to dispensing

L07-33

n/a

n/a

n/a

12/28/07

JED

Returned from dispensing

L07-33

34.96

4.86

30.10

1/7/08

JED

Removed to dispensing

A08-05

n/a

n/a

n/a

1/7/08

JED

Returned from dispensing

A08-05

14.96

4.86

10.10

2/12/08

PWM

Removed to dispensing

B08-13

n/a

n/a

n/a

2/12/08

PWM

Returned from dispensing

B08-13

4.92

4.86

0.04

* From package label ** Calculated

Time limitations on production

“When appropriate, time limits for the completion of each phase of production shall be established to assure the quality of the drug product..”

Specification: 0.05%

Time Limit for Drying step: 10 hours

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Control of Microbiological Contamination

Physical controls:

  • Non-sterile: - hair nets, gloves, tyvek suits

- filtered supply air to work areas

  • Sterile - clean rooms with controlled, monitored particulates levels

- equipment sterilization

- product sterilization process

Procedural controls:

  • Appropriate written procedures which are designed to prevent objectionable microorganisms in drug products

For example: Gowning Procedures

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Annual Review of Records

  • Evaluate each drug product manufactured
  • Number and types of deviations
  • Number of failed batches
  • Trend in data
  • Reasons for customer complaints,

recalls and returned goods

  • Need to change specifications or production procedures?
  • Need to train personnel?

*

Complaints, Recalls, & Returned Goods

Responsible officials of the firm, must be aware of all complaints, recalls, and returned goods.

Complaints – usually made by consumers directly to drug company. Any adverse experiences must be reported by the company to FDA.

Recalls – most are “voluntary”, when a serious problem is discovered by the drug company or identified by FDA during an inspection.

Returned Goods – quite often for damage to packaging (potential for contamination).

A company must maintain files of all the complaints, recalls and returned goods

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Complaints, Recalls, & Returned Goods

Recall Classifications

  • Class I: Dangerous or defective products that predictably could cause serious health problems or death. Examples include: food found to contain botulinum toxin, food with undeclared allergens, a label mix-up on a lifesaving drug, or a defective artificial heart valve.

  • Class II: Products that might cause a temporary health problem, or pose only a slight threat of a serious nature. Example: a drug that is under-strength but that is not used to treat life-threatening situations.

  • Class III: Products that are unlikely to cause any adverse health reaction, but that violate FDA labeling or manufacturing laws. Examples include: a minor container defect and lack of English labeling in a retail food

*

Distribution Records

  • A company must keep accurate documentation of the distribution of their products
  • Which product
  • Which lot number
  • To whom
  • When
  • An effective recall would be difficult without this information

*

Subpart F Production and Process Controls

    § 211.100 - Written procedures; deviations
   § 211.101 - Charge-in of components
   § 211.103 - Calculation of yield
   § 211.105 - Equipment identification
   § 211.110 - Sampling and testing of in-process materials and
drug products
   § 211.111 - Time limitations on production
   § 211.113 - Control of microbiological contamination
   § 211.115 - Reprocessing

*

Subpart J Records and Reports

    § 211.180 - General requirements
   § 211.182 - Equipment cleaning and use log
   § 211.184 - Component, drug product container, closure, and

labeling records
   § 211.186 - Master production and control records
   § 211.188 - Batch production and control records
   § 211.192 - Production record review
   § 211.194 - Laboratory records
   § 211.196 - Distribution records
   § 211.198 - Complaint files

*

Good manufacturing Practices

GMPs are not just a set of regulations

They are a philosophy / a way of life

A culture which is developed and nurtured over time

For example:

*

Consider this Scenario

Situation: An operator is about to charge a component into a reactor and notices that there is a stain at the bottom of the reactor.

What does he do?

His options:

Ignore it because management has been pushing to get the project back on schedule

Ignore it because his buddy was the one who cleaned it and he doesn’t want to get him in trouble.

Notify his supervisor and start an investigation

  • Root Cause: the glass lining had cracked and the carbon steel shell had started to corrode. The rust would have contaminated the batch (putting the project very far behind schedule). The integrity of the reactor was compromised and could have resulted in catastrophic failure when pressurized.

*

Consider this Scenario

Situation: An operator is about to charge a component into a reactor and notices that there is a stain at the bottom of the reactor.

His options:

Ignore it because management has been pushing to get the project back on schedule

Ignore it because his buddy was the one who cleaned it and he doesn’t want to get him in trouble.

Notify his supervisor and start an investigation

  • Root Cause: the glass lining had cracked and the carbon steel shell had started to corrode. The rust would have contaminated the batch (putting the project very far behind schedule). The integrity of the reactor was compromised and could have resulted in catastrophic failure when pressurized.

*

Consider this Scenario

Situation: An operator is about to charge a component into a reactor and notices that there is a stain at the bottom of the reactor.

His options:

Ignore it because management has been pushing to get the project back on schedule

Ignore it because his buddy was the one who cleaned the reactor and he doesn’t want to get him in trouble.

Notify his supervisor and start an investigation

  • Root Cause: the glass lining had cracked and the carbon steel shell had started to corrode. The rust would have contaminated the batch (putting the project very far behind schedule). The integrity of the reactor was compromised and could have resulted in catastrophic failure when pressurized.

*

Consider this Scenario

Situation: An operator is about to charge a component into a reactor and notices that there is a stain at the bottom of the reactor.

His options:

Ignore it because management has been pushing to get the project back on schedule

Ignore it because his buddy was the one who cleaned the reactor and he doesn’t want to get him in trouble.

Notify his supervisor and start an investigation

He chose the latter option, luckily….

  • Root Cause: the glass lining had cracked and the carbon steel shell had started to corrode. The rust would have contaminated the batch (putting the project very far behind schedule). The integrity of the reactor was compromised and could have resulted in catastrophic failure when pressurized.

*

Consider this Scenario

Root Cause:

The glass lining had cracked and the carbon steel shell had started to corrode. The rust would have contaminated the batch (putting the project very far behind schedule). The integrity of the reactor was compromised and could have resulted in catastrophic failure when pressurized.

*

Novelle Pharmaceuticals, Inc.

Batch Record for the Formulation of

Newdrug

®

50mg Dimethylchickenwire Coated Tablets

Product Number: NPI-034

Stock Number: 28092

Nominal Batch Size: 1,200,000 tablets

Lot Number: ____________

Effective Date:

Version: 2

Written / Revised By: __________________ Date: __________ Issue Date: __________

Technical Reviewer: __________________ Date: __________ Issued By: __________

QA Appproval: __________________ Date: __________ Production Start Date: __________

Novelle Pharmaceuticals, Inc.

Batch Record for the Formulation of

Newdrug

®

50mg Dimethylchickenwire Coated Tablets

Product Number: NPI-034

Stock Number: 28092

Nominal Batch Size: 1,200,000 tablets

Lot Number: ____________

Effective Date:

Version: 2

Written / Revised By: __________________ Date: __________ Issue Date: __________

Technical Reviewer: __________________ Date: __________ Issued By: __________

QA Appproval: __________________ Date: __________ Production Start Date: __________

Novelle Pharmaceuticals, Inc.

Batch Record for the Formulation of

Newdrug

®

50mg Dimethylchickenwire Coated Tablets

Product Number: NPI-034

Stock Number: 28092

Nominal Batch Size: 1,200,000 tablets

Lot Number: ____________

Effective Date:

Version: 2

Written / Revised By: __________________ Date: __________ Issue Date: __________

Technical Reviewer: __________________ Date: __________ Issued By: __________

QA Appproval: __________________ Date: __________ Production Start Date: __________

Step Action Initials Date / Time

23

Close the hatch on Blender EQ17 B and blend the mixture for

14 minutes ± 2 minutes.

Start Time: __________

End Time: __________

Total Blend Time: __________

_________

_______________

Novelle Pharmaceuticals, Inc.

Master Batch Record for the Formulation of Newdrug

®

50mg Coated Tablets

LOT NUMBER: ___________ EFFECTIVE DATE: __________

STOCK NUMBER: 28092 REVISION NUMBER: 2

PRODUCT NUMBER: NPI-034 Page 17 of 42

Step Action Initials Date / Time

22

Charge 60.00 kg of dimethylchickenwire, stock number

2463, into blender EQ17B.

Gross Weight: _______ kg Stock Number: ________

Tare Weight: _______ kg Lot Number: ________

Net Weight: _______kg

__________

__________

________________

________________

Novelle Pharmaceuticals, Inc.

Batch Record for the Formulation of Newdrug

®

50mg Dimethylchickenwire Coated Tablets

LOT NUMBER: ___________ EFFECTIVE DATE: __________

STOCK NUMBER: 28092 REVISION NUMBER: 2

PRODUCT NUMBER: NPI-034 Page 16 of 42

Blender EQ17B Log Sheet

Start

Date

Activity Lot No. /

WO No.

Product End

Date

Clean/Maint

Disposition

Init /

Date*

Init /

Date*

1/13/08 Production A08-12 ColdMed

10 mg

1/18/08 n/a

1/21/08 Partial Clean A08C-07 n/a 1/22/08 pass GEJ

1/22/08

EHD

1/22/08

1/23/08 Production A08-33 ColdMed

25 mg

1/28/08 n/a

1/29/08 Full Clean B08C-06 n/a 2/1/08 Pass GEJ

2/1/08

EHD

2/1/08

2/1/08 Replace spray

nozzles

WO-1435 n/a 2/3 Complete MM

2/3/08

EHD

2/3/08

2/4/08 Maint. Clean B08C-06 n/a 2/6/08 Pass LSP

2/6/08

KKT

2/6/08

2/11/08 Production B08-13 NewDrug

50mg

*Required to confirm maintenance and cleaning

Component name: Microcrystalline Cellulose Receiving Code: 1782667

Grade: Food Grade Date of Receipt: Dec 13, 2007

Supplier name: J.T. Baker Supplier Lot number: MC113D

Manufacturer name: BulkChem Company Manufacturer Lot number: n/a

Quantity received: 6 x 50kg drums

Disposition: Approved Date: Dec 21, 2007

Container No. __1__ of __6__ Tare wt. (from package label): ___4.86__ kg

Date Initials Activity Batch

Number

Gross

(kg)

Tare *

(kg)

Net **

(kg)

12/13/07

T J K

Receipt

54.98 4.86 50.12

12/14/07

LT

Remove QC Sample

54.96 4.86 50.10

12/28/07

JED

Removed to dispensing L07-33

n/a n/a n/a

12/28/07

JED

Returned from dispensing L07-33

34.96 4.86 30.10

1/7/08

JED

Removed to dispensing A08-05

n/a n/a n/a

1/7/08

JED

Returned from dispensing A08-05

14.96 4.86 10.10

2/12/08

PWM

Removed to dispensing B08-13

n/a n/a n/a

2/12/08

PWM

Returned from dispensing B08-13

4.92 4.86 0.04

* From package label ** Calculated

No

Blend

Granulate

Dry

<2%

H

2

O?

Yes

Mill

Blend

Compress

Homo

-

geneous?

Yes

No

Coat