Problems in tablet manufacturing

Problems & remedy in tablet manufacturing process from GRANULATION TO COATING

Problems in tablet manufacturing

Introduction

An ideal tablet should be free from any visual defect or functional defect. The advancements and innovations in tablet manufacture have not decreased the problems, often encountered in the production, instead have increased the problems, mainly because of the complexities of tablet presses; and/or the greater demands of quality.

An industrial pharmacist usually encounters number of problems during manufacturing. Majority of visual defects are due to inadequate fines or inadequate moisture in the granules ready for compression or due to faulty machine setting. Functional defects are due to faulty formulation. Solving many of the manufacturing problems requires an in–depth knowledge of granulation processing and tablet presses, and is acquired only through an exhaustive study and a rich experience.

Here, we will discuss the imperfections found in tablets along–with their causes and related remedies. The imperfections are known as: ‘VISUAL DEFECTS’ and they are either related to imperfections in any one or more of the following factors:

I. Tableting Process

II. Excipient

III. Machine

The defects related to Tableting Process are as follows:

i) CAPPING: It is partial or complete separation of the top or bottom of tablet due air-entrapment in the granular material.

ii) LAMINATION: It is separation of tablet into two or more layers due to air-entrapment in the granular material.

iii) CRACKING: It is due to rapid expansion of tablets when deep concave punches are used.

The defects related to Excipient are as follows:

iv) CHIPPING: It is due to very dry granules.

v) STICKING: It is the adhesion of granulation material to the die wall

vi) PICKING: It is the removal of material from the surface of tablet and its adherance to the face of punch.

vii) BINDING

These problems (v, vi, vii) are due to more amount of binder in the granules or wet granules.

The defect related to more than one factor:

viii) MOTTLING: It is either due to any one or more of these factors: Due to a coloured drug, which has different colour than the rest of the granular material? (Excipient- related); improper mixing of granular material (Process-related); dirt in the granular material or on punch faces; oil spots by using oily lubricant.

The defect related to Machine

ix)DOUBLE IMPRESSION: It is due to free rotation of the punches, which have some engraving on the punch faces.

Further, in this section, each problem is described along-with its causes and remedies which may be related to either of formulation (granulation) or of machine (dies, punches and entire tablet press).

Capping

‘Capping’ is the term used, when the upper or lower segment of the tablet separates horizontally, either partially or completely from the main body of a tablet and comes off as a cap, during ejection from the tablet press, or during subsequent handling.

Reason: Capping is usually due to the air–entrapment in a compact during compression, and subsequent expansion of tablet on ejection of a tablet from a die.

THE CAUSES AND REMEDIES OF CAPPING RELATED TO ‘FORMULATION’ (GRANULATION)

Sr. No.	CAUSES	REMEDIES
1.	Large amount of fines in the granulation	Remove some or all fines through 100 to 200 mesh screen
2.	Too dry or very low moisture content (leading to loss of proper binding action).	Moisten the granules suitably. Add hygroscopic substance e.g.: sorbitol, methyl- cellulose or PEG-4000.
3.	Not thoroughly dried granules.	Dry the granules properly.
4.	Insufficient amount of binder or improper binder.	Increasing the mount of binder OR Adding dry binder such as pre-gelatinized starch, gum acacia, powdered sorbitol, PVP, hydrophilic silica or powdered sugar.
5.	Insufficient or improper lubricant.	Increase the amount of lubricant or change the type of lubricant.
6.	Granular mass too cold to compress firm.	Compress at room temperature.

THE CAUSES AND REMEDIES OF CAPPING RELATED TO ‘MACHINE’ (DIES, PUNCHES AND TABLET PRESS)

Sr. No.	CAUSES	REMEDIES
1.	Poorly finished dies	Polish dies properly. Investigate other steels or other materials.
2.	Deep concave punches or beveled-edge faces of punches.	Use flat punches.
3.	Lower punch remains below the face of die during ejection.	Make proper setting of lower punch during ejection.
4.	Incorrect adjustment of sweep-off blade.	Adjust sweep-off blade correctly to facilitate proper ejection.
5.	High turret speed.	Reduce speed of turret (Increase dwell time).

Lamination / Laminating

Definition: ‘Lamination’ is the separation of a tablet into two or more distinct horizontal layers.

Reason: Air–entrapment during compression and subsequent release on ejection.

The condition is exaggerated by higher speed of turret.

THE CAUSES AND REMEDIES OF LAMINATION RELATED TO FORMULATION (GRANULATION)

Sr. No.	CAUSES	REMEDIES
1.	Oily or waxy materials in granules	Modify mixing process. Add adsorbent or absorbent.
2.	Too much of hydrophobic lubricant e.g.: Magnesium-stearate.	Use a less amount of lubricant or change the type of lubricant.

The Causes and Remedies of Lamination related to MACHINE (Dies, Punches and Tablet Press)

Sr. No.	CAUSES	REMEDIES</ b>
1.	Rapid relaxation of the peripheral regions of a tablet, on ejection from a die.	Use tapered dies, i.e. upper part of the die bore has an outward taper of 3° to 5°.
2.	Rapid decompression	Use pre-compression step. Reduce turret speed and reduce the final compression pressure.

Chipping

Definition: ‘Chipping’ is defined as the breaking of tablet edges, while the tablet leaves the press or during subsequent handling and coating operations.

Reason: Incorrect machine settings, specially mis-set ejection take-off.

THE CAUSES AND REMEDIES OF CHIPPING RELATED TO FORMULATION (GRANULATION) ARE AS FOLLOWS

Sr. No.	CAUSES	REMEDIES
1.	Sticking on punch faces	Dry the granules properly or increase lubrication.
2.	Too dry granules.	Moisten the granules to plasticize. Add hygroscopic substances.
3.	Too much binding causes chipping at bottom.	Optimize binding, or use dry binders.

THE CAUSES AND REMEDIES OF CHIPPING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS)

Sr. No.	CAUSES	REMEDIES
1.	Groove of die worn at compression point.	Polish to open end, reverse or replace the die.
2.	Barreled die (center of the die wider than ends)	Polish the die to make it cylindrical
3.	Edge of punch face turned inside/inward.	Polish the punch edges
4.	Concavity too deep to compress properly.	Reduce concavity of punch faces. Use flat punches.

Cracking

Definition: Small, fine cracks observed on the upper and lower central surface of tablets, or very rarely on the sidewall are referred to as ‘Cracks’.

Reason: It is observed as a result of rapid expansion of tablets, especially when deep concave punches are used.

THE CAUSES AND REMEDIES OF CRACKING RELATED TO FORMULATION (GRANULATION)

Sr. No.	CAUSES	REMEDIES
1.	Large size of granules.	Reduce granule size. Add fines.
2.	Too dry granules.	Moisten the granules properly and add proper amount of binder.
3.	Tablets expand.	Improve granulation. Add dry binders.
4.	Granulation too cold.	Compress at room temperature.

THE CAUSES AND REMEDIES OF CRACKING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS)

Sr. No.	CAUSES	REMEDIES
1.	Tablet expands on ejection due to air entrapment.	Use tapered die.
2.	Deep concavities cause cracking while removing tablets	Use special take-off.

Sticking / Filming

(1)

Definition: ‘Sticking’ refers to the tablet material adhering to the die wall.

Filming is a slow form of sticking and is largely due to excess moisture in the granulation.

Reason: Improperly dried or improperly lubricated granules.

THE CAUSES AND REMEDIES OF STICKING RELATED TO FORMULATION (GRANULATION)

Sr. No.	CAUSES	REMEDIES
1.	Granules not dried properly.	Dry the granules properly. Make moisture analysis to determine limits.
2.	Too little or improper lubrication.	Increase or change lubricant.
3.	Too much binder	Reduce the amount of binder or use a different type of binder.
4.	Hygroscopic granular material.	Modify granulation and compress under controlled humidity.
5.	Oily or way materials	Modify mixing process. Add an absorbent.
6.	Too soft or weak granules.	Optimize the amount of binder and granulation technique.

THE CAUSES AND REMEDIES OF STICKING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS)

Sr. No.	CAUSES	REMEDIES
1.	Concavity too deep for granulation.	Reduce concavity to optimum.
2.	Too little pressure.	Increase pressure.
3.	Compressing too fast.	Reduce speed.

Picking

Definition: ‘Picking’ is the term used when a small amount of material from a tablet is sticking to and being removed off from the tablet-surface by a punch face.

The problem is more prevalent on the upper punch faces than on the lower ones. The problem worsens, if tablets are repeatedly manufactured in this station of tooling because of the more and more material getting added to the already stuck material on the punch face.

Reason: Picking is of particular concern when punch tips have engraving or embossing letters, as well as the granular material is improperly dried.

THE CAUSES AND REMEDIES OF PICKING RELATED TO FORMULATION (GRANULATION)

Sr. No.	CAUSES	REMEDIES
1.	Excessive moisture in granules.	Dry properly the granules, determine optimum limit.
2.	Too little or improper lubrication.	Increase lubrication; use colloidal silica as a ‘polishing agent’, so that material does not cling to punch faces.
3.	Low melting point substances, may soften from the heat of compression and lead to picking.	Add high melting-point materials. Use high meting point lubricants.
4.	Low melting point medicament in high concentration.	Refrigerate granules and the entire tablet press.
5.	Too warm granules when compressing.	Compress at room temperature. Cool sufficiently before compression.
6.	Too much amount of binder.	Reduce the amount of binder, change the type or use dry binders.

THE CAUSES AND REMEDIES OF PICKING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS)

Sr. No.	CAUSES	REMEDIES
1.	Rough or scratched punch faces.	Polish faces to high luster.
2.	Embossing or engraving letters on punch faces such as B, A, O, R, P, Q, G.	Design lettering as large as possible. Plate the punch faces with chromium to produce a smooth and non-adherent face.
3.	Bevels or dividing lines too deep.	Reduce depths and sharpness.
4.	Pressure applied is not enough; too soft tablets.	Increase pressure to optimum.

Binding

Definition: ‘Binding’ in the die, is the term used when the tablets adhere, seize or tear in the die. A film is formed in the die and ejection of tablet is hindered. With excessive binding, the tablet sides are cracked and it may crumble apart.

Reason: Binding is usually due to excessive amount of moisture in granules, lack of lubrication and/or use of worn dies.

THE CAUSES AND REMEDIES OF BINDING RELATED TO FORMULATION (GRANULATION)

Sr. No.	CAUSES	REMEDIES
1.	Too moist granules and extrudes around lower punch.	Dry the granules properly.
2.	Insufficient or improper lubricant.	Increase the amount of lubricant or use a more effective lubricant.
3.	Too coarse granules.	Reduce granular size, add more fines, and increase the quantity of lubricant.
4.	Too hard granules for the lubricant to be effective.	Modify granulation. Reduce granular size.
5.	Granular material very abrasive and cutting into dies.	If coarse granules, reduce its size. Use wear-resistant dies.
6.	Granular material too warm, sticks to the die.	Reduce temperature. Increase clearance if it is extruding.

THE CAUSES AND REMEDIES OF BINDING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS)

Sr. No.	CAUSES	REMEDIES
1.	Poorly finished dies.	Polish the dies properly.
2.	Rough dies due to abrasion, corrosion.	Investigate other steels or other materials or modify granulation.
3.	Undersized dies. Too little clearance.	Rework to proper size. Increase clearance.
4.	Too much pressure in the tablet press.	Reduce pressure. OR Modify granulation.

Mottling

(1)

Definition: ‘Mottling’ is the term used to describe an unequal distribution of colour on a tablet, with light or dark spots standing out in an otherwise uniform surface.

Reason: One cause of mottling may be a coloured drug, whose colour differs from the colour of excipients used for granulation of a tablet.

 THE CAUSES AND REMEDIES OF MOTTLING

Sr. No.	CAUSES	REMEDIES
1.	A coloured drug used along with colourless or white-coloured excipients.	Use appropriate colourants.
2.	A dye migrates to the surface of granulation while drying.	Change the solvent system, Change the binder, Reduce drying temperature and Use a smaller particle size.
3.	Improperly mixed dye, especially during ‘Direct Compression’.	Mix properly and reduce size if it is of a larger size to prevent segregation.
4.	Improper mixing of a coloured binder solution.	Incorporate dry colour additive during powder blending step, then add fine powdered adhesives such as acacia and tragacanth and mix well and finally add granulating liquid.

Double impression

(1)

Definition: ‘Double Impression’ involves only those punches, which have a monogram or other engraving on them.

Reason: At the moment of compression, the tablet receives the imprint of the punch. Now, on some machines, the lower punch freely drops and travels uncontrolled for a short distance before riding up the ejection cam to push the tablet out of the die, now during this free travel, the punch rotates and at this point, the punch may make a new impression on the bottom of the tablet, resulting in ‘Double Impression’.

If the upper punch is uncontrolled, it can rotate during the short travel to the final compression stage and create a double impression.

THE CAUSES AND REMEDIES OF DOUBLE IMPRESSION

Sr. No.	CAUSE	REMEDIES
1.	Free rotation of either upper punch or lower punch during ejection of a tablet.	-Use keying in tooling, i.e. inset a key alongside of the    punch, so that it fits the punch and prevents punch rotation. -Newer presses have anti-turning devices, which prevent punch rotation.

Problems and remedies for tablet coating

Blistering

Definition: It is local detachment of film from the substrate forming blister.

Reason: Entrapment of gases in or underneath the film due to overheating either during spraying or at the end of the coating run.

 THE CAUSE AND REMEDY OF BLISTERING

Sr. No.	CAUSE	REMEDY
1.	Effect of temperature on the strength, elasticity and adhesion of the film.	Use mild drying condition.

Chipping

Definition: It is defect where the film becomes chipped and dented, usually at the edges of the tablet.

Reason: Decrease in fluidizing air or speed of rotation of the drum in pan coating.

THE CAUSE AND REMEDY OF CHIPPING

Sr. No.	CAUSE	REMEDY
1.	High degree of attrition associated with the coating process.	Increase hardness of the film by increasing the molecular weight grade of polymer.

Cratering

Definition: It is defect of film coating whereby volcanic-like craters appears exposing the tablet surface.

Reason: The coating solution penetrates the surface of the tablet, often at the crown where the surface is more porous, causing localized disintegration of the core and disruption of the coating.

 THE CAUSES AND REMEDIES OF CRATERING

Sr. No.	CAUSES	REMEDIES
1.	Inefficient drying.	Use efficient and optimum drying conditions.
2.	Higher rate of application of coating solution.	Increase viscosity of coating solution to decrease spray application rate.

Picking

Definition: It is defect where isolated areas of film are pulled away from the surface when the tablet sticks together and then part.

Reason: Conditions similar to cratering that produces an overly wet tablet bed where adjacent tablets can stick together and then break apart.

 THE CAUSES AND REMEDIES OF PICKING

Sr. No.	CAUSE	REMEDY
1.	Inefficient drying.	Use optimum and efficient drying conditions or increase the inlet air temperature.
2.	Higher rate of application of coating solution	Decrease the rater of application of coating solution by increasing viscosity of coating solution.

Pitting

Definition: It is defect whereby pits occur in the surface of a tablet core without any visible disruption of the film coating.

Reason: Temperature of the tablet core is greater than the melting point of the materials used in the tablet formulation.

 THE CAUSE AND REMEDY OF PITTING

Sr. No.	CAUSE	REMEDY
1.	Inappropriate drying (inlet air ) temperature	Dispensing with preheating procedures at the initiation of coating and modifying the drying (inlet air) temperature such that the temperature of the tablet core is not greater than the melting point of the batch of additives used.

Blooming

Definition: It is defect where coating becomes dull immediately or after prolonged storage at high temperatures.

Reason: It is due to collection on the surface of low molecular weight ingredients included in the coating formulation. In most circumstances the ingredient will be plasticizer.

 THE CAUSE AND REMEDY OF BLOOMING

Sr. No.	CAUSE	REMEDY
1.	High concentration and low molecular weight of plasticizer.	Decrease plasticizer concentration and increase molecular weight of plasticizer.

Blushing

Definition: It is defect best described as whitish specks or haziness in the film.

Reason: It is thought to be due to precipitated polymer exacerbated by the use of high coating temperature at or above the thermal gelation temperature of the polymers.

THE CAUSES AND REMEDIES OF BLUSHING

Sr. No.	CAUSES	REMEDIES
1.	High coating temperature	Decrease the drying air temperature
2.	Use of sorbitol in formulation which causes largest fall in the thermal gelation temperature of the Hydroxy Propyl Cellulose, Hydroxy Propyl Methyl Cellulose, Methyl Cellulose and Cellulose ethers.	Avoid use of sorbitol with Hydroxy Propyl Cellulose, Hydroxy Propyl Methyl Cellulose, Methyl Cellulose and Cellulose ethers.

Colour variation

Definition: A defect which involves variation in colour of the film.

Reason: Alteration of the frequency and duration of appearance of tablets in the spray zone or the size/shape of the spray zone.

 THE CAUSE AND REMEDY OF COLOUR VARIATION

Sr. No.	CAUSE	REMEDY
1.	Improper mixing, uneven spray pattern, insufficient coating, migration of soluble dyes-plasticizers and other additives during drying.	Go for geometric mixing, reformulation with different plasticizers and additives or use mild drying conditions.

Infilling

Definition: It is defect that renders the intagliations indistinctness.

Reason: Inability of foam, formed by air spraying of a polymer solution, to break. The foam droplets on the surface of the tablet breakdown readily due to attrition but the intagliations form a protected area allowing the foam to accumulate and “set”. Once the foam has accumulated to a level approaching the outer contour of the tablet surface, normal attrition can occur allowing the structure to be covered with a continuous film.

 THE CAUSE AND REMEDY OF INFILLING

Sr. No.	CAUSE	REMEDY
1.	Bubble or foam formation because of air spraying of a polymer solution	Add alcohol or use spray nozzle capable of finer atomization.

Orange peel/Roughness

Definition: It is surface defect resulting in the film being rough and nonglossy. Appearance is similar to that of an orange.

Reason: Inadequate spreading of the coating solution before drying.

THE CAUSES AND REMEDIES OF ORANGE PEEL/ROUGHNESS

Sr. No.	CAUSES	REMEDIES
1.	Rapid Drying	Use mild drying conditions
2.	High solution viscosity	Use additional solvents to decrease viscosity of solution.

Cracking/Splitting

Definition: It is defect in which the film either cracks across the crown of the tablet (cracking) or splits around the edges of the tablet (Splitting)

Reason: Internal stress in the film exceeds tensile strength of the film.

THE CAUSE AND REMEDY OF CRACKING/SPLITTING

Sr. No.	CAUSE	REMEDY
1.	Use of higher molecular weight polymers or polymeric blends.	Use lower molecular weight polymers or polymeric blends.  Also adjust plasticizer type and concentration.

Key Phrases

• During tablet manufacture, an industrial pharmacist usually encounters many problems. Solving these problems requires an in-depth knowledge of tablet-formulation as well as machine-operating processes.

• Capping and Lamination are the defects arising as a result of air-entrapment in the granular material.

• Chipping is a defect related arising due to very dry granules.

• Cracking is due to rapid expansion of tablets, when deep concave punches are used.

• Sticking, Picking and Binding are the imperfections related to more amount of binder in granules.

• Mottling is an imperfection arising due to more than one factor: a coloured drug, dirt in granules or the use of an oily lubricant.

• Double-Impression is related to a machine defect: it is caused by the free rotation of punches that have some engraving on the punch-faces.

Coating defects:

• Blistering is related to entrapment of gases in or underneath the film due to overheating either during spraying or at the end of the coating run. Use of mild drying conditions can solve this problem.

• Chipping is related to higher degree of attrition associated with the coating process. Increase in hardness of the film by increasing the molecular weight grade of polymer can solve this problem.

• Cratering is related to penetration of the coating solution into the surface of the tablet, often at the crown where the surface is more porous, causing localized disintegration of the core and disruption of the coating. Decrease in spray application rate and use of optimum and efficient drying conditions can solve this problem.

• Pitting is defect in which temperature of the tablet core is greater than the melting point of the materials used in tablet formulation. Dispensing with preheating procedures at the initiation of coating and modifying the drying (inlet air) temperature can solve this problem.

• Blooming or dull film is generally because of higher concentration and lower molecular weight of plasticizer. So use lower concentration and higher molecular grade of plasticizer.

• Blushing/Whitish specks/Haziness of the film is related to precipitation of polymer exacerbated by the use of high coating temperature at or above the thermal gelation temperature of the polymers.

• Colour variation is because of improper mixing, uneven spray pattern, insufficient coating or migration of soluble dyes during drying. Geometric mixing, mild drying conditions and reformulation with different plasticizers can solve this problem.

• Infilling is because of bubble/foam formation during air spraying of a polymer solution. Addition of alcohol or use of spray nozzle capable of finer atomization can solve this problem.

• Orange peel/Roughness is related to inadequate spreading of the coating solution before drying. So decrease in viscosity of coating solution can counter this defect.

• Cracking is seen when internal stresses in the film exceeds tensile strength of the film. This is common with higher molecular weight polymers or polymeric blends. So use lower molecular weight polymers or polymeric blends

Questioner and Answer Q8, Q9, Q10

Guidance for Industry
Q8, Q9, and Q10
Questions and Answers(R4)
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
November 2011
ICH
Revision 1
Guidance for Industry
Q8, Q9, and Q10
Questions and Answers(R4)
Additional copies are available from:
Office of Communications
Division of Drug Information, WO51, Room 2201
Center for Drug Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave.Silver Spring, MD 20993-0002
Phone: 301-796-3400; Fax: 301-847-8714
druginfo@fda.hhs.gov
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
and/or
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(Tel) 800-835-4709 or 301-827-1800
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
November 2011
ICH
Revision 1
TABLE OF CONTENTS
I.
INTRODUCTION (1)
.......................................................................................................
1
II.
QUESTIONS AND ANSWERS
.......................................................................................
2
A.
For General Clarification (1.1)
.....................................................................................................
2
B.
Quality by Design (QbD) Topics (2)
.............................................................................................
3
1.
Design Space (2.1)
...........................................................................................................................
3
2.
Real-Time Release Testing (2.2)
......................................................................................................
5
3.
Control Strategy (2.3)
......................................................................................................................
7
C.
Pharmaceutical Quality System (3)
..............................................................................................
9
D.
Impact of New ICH Quality Guidance on GMP Inspection Practices (4)
..............................
11
E.
Knowledge Management (5)
.......................................................................................................
11
F.
Software Solutions (6)
..................................................................................................................
13
Contains Nonbinding Recommendations
Guidance for Industry1
Q8, Q9, and Q10
Questions and Answers(R4)
This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance.
I. INTRODUCTION (1)2
Since the Q8, Q9, and Q10 guidances were made final, experiences implementing the guidances in the ICH regions have given rise to requests for clarification. This question and answer (Q&A) document is intended to clarify key issues. The guidance reflects the current working procedure of the ICH Quality Implementation Working Group (Q-IWG) for implementing the Q8, Q9, and Q10 guidances.
This guidance is a revision of the ICH guidance titled Q8, Q9, and Q10 Questions and Answers (May 2010). In November 2010, the May 2010 guidance was revised to add Q&A9 to section
II.B.1 Design Space (2.1).
The benefits of harmonizing technical requirements across the ICH regions can be realized only if the various quality ICH guidances are implemented and interpreted in a consistent way across the three regions. The Q-IWG is tasked to develop Q&As to facilitate implementation of existing quality guidance.
The Q&As reference the following ICH guidances available on the Internet at
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
under International Conference on Harmonisation — Quality:
1 This guidance was developed within the Quality Implementation Working Group of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been subject to consultation by the regulatory parties, in accordance with the ICH process. The Q&As in this document have been endorsed by the ICH Steering Committee at Step 4 of the ICH process, April 2009, June 2009, October 2009, and November 2010. At Step 4 of the process, the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan, and the United States.
2 Arabic numbers reflect the organizational breakdown of the document endorsed by the ICH Steering Committee at Step 4 of the ICH process, November 2010.
1
Contains Nonbinding Recommendations
•
Q8 (R2) Pharmaceutical Development (includes the Q8 parent guidance (Part I) and the annex (Part II), which provides further clarification of the Q8 parent guidance and describes the principles of quality by design)
•
Q9 Quality Risk Management
•
Q10 Pharmaceutical Quality System
FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.
II. QUESTIONS AND ANSWERS
A. For General Clarification (1.1)
Q1: Is the minimal approach accepted by regulators?
A1: Yes. The minimal approach as defined in Q8(R2) (sometime also called “baseline” or “traditional” approach) is the expectation that is to be achieved for a fully acceptable submission. However, the “enhanced” approach as described in ICH Q8(R2) is encouraged (Ref. Q8(R2) Annex, appendix 1). (Approved June 2009)
Q2: What is an appropriate approach for process validation using ICH Q8, Q9, and Q10?
A2: The objectives of process validation are unchanged when using ICH Q8, Q9, and Q10. The main objective of process validation remains that a process design yields a product meeting its predefined quality criteria. ICH Q8, Q9, and Q10 provide a structured way to define product critical quality attributes, design space, the manufacturing process, and the control strategy. This information can be used to identify the type and focus of studies to be performed prior to and on initial commercial production batches. As an alternative to the traditional process validation, continuous process verification (see definition in ICH Q8(R2) glossary) can be utilized in process validation protocols for the initial commercial production and for manufacturing process changes for the continual improvement throughout the remainder of the product lifecycle. (Approved October 2009)
Q3: How can information from risk management and continuous process verification provide for a robust continual improvement approach under ICH Q8, Q9 and Q10?
2
Contains Nonbinding Recommendations
A3: Like the product itself, process validation also has a lifecycle (process design, process qualification and ongoing process verification). A risk assessment conducted prior to initial commercial validation batches can highlight the areas where particular focus and data collection could demonstrate the desired high level of assurance of commercial process robustness. Continual monitoring (e.g., via continuous process verification) can further demonstrate the actual level of assurance of process consistency and provide the basis for continual improvement of the product. Quality Risk Management methodologies of ICH Q9 can be applied throughout the product lifecycle to maintain a state of process control. (Approved October 2009)
B. Quality by Design (QbD) Topics (2)
Q1: Is it always necessary to have a design space (DS) or real-time release (RTR) testing to implement QbD?
A1: Under Quality by Design, establishing a design space or using real-time release testing is not necessarily expected (ICH Q8(R2)). (Approved April 2009)
1. Design Space (2.1)
Q1: Is it necessary to study multivariate interactions of all parameters to develop a design space?
A1: No, the applicant should justify the choice of material attributes and parameters for multivariate experimentation based on risk assessment and desired operational flexibility. (Approved April 2009)
Q2: Can a design space be applicable to scale-up?
A2: Yes, when appropriately justified (for additional details, see Q8(R2) Annex section II.D.4 (2.4.4)). An example of a scale-independent design space is provided in the European Federation of Pharmaceutical Industries and Associations (EFPIA) Mock P2 document (EFPIA Mock P2 submission on “Examplain”: Chris Potter, Rafael Beerbohm, Alastair Coupe, Fritz Erni, Gerd Fischer, Staffan Folestad, Gordon Muirhead, Stephan Roenninger, Alistair Swanson, A guide to EFPIA’s “Mock P.2” Document, Pharm. Tech. (Europe), 18, December 2006, 39-44).
This example may not reflect the full regulatory requirements for a scale-up. (Approved April 2009)
Q3: Can a design space be applicable to a site change?
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A3: Yes, it is possible to justify a site change using a site independent design space based on a demonstrated understanding of the robustness of the process and an in depth consideration of site specific factors (e.g., equipment, personnel, utilities, manufacturing environment, and equipment). There are region specific regulatory requirements associated with site changes that need to be followed. (Approved April 2009)
Q4: Can a design space be developed for single and/or multiple unit operations?
A4: Yes, it is possible to develop a design space for single unit operations or across a series of unit operations (see Q8(R2) Annex, section II.D.3 (2.4.3)). (Approved April 2009)
Q5 Is it possible to develop a design space for existing products?
A5: Yes, it is possible. Manufacturing data and process knowledge can be used to support a design space for existing products. Relevant information should be utilized from e.g., commercial scale manufacturing, process improvement, corrective and preventive action (CAPA), and development data.
For manufacturing operations run under narrow operational ranges in fixed equipment, an expanded region of operation and an understanding of multiparameter interactions may not be achievable from existing manufacturing data alone and additional studies may provide the information to develop a design space. Sufficient knowledge should be demonstrated, and the design space should be supported experimentally to investigate interactions and establish parameter/attribute ranges. (Approved April 2009)
Q6: Is there a regulatory expectation to develop a design space for an existing product?
A6: No, development of design space for existing products is not necessary unless the applicant has a specific need and desires to use a design space as a means to achieve a higher degree of product and process understanding. This may increase manufacturing flexibility and/or robustness. (Approved April 2009)
Q7: Can a design space be applicable to formulation?
A7: Yes, it may be possible to develop formulation (not component but rather composition) design space consisting of the ranges of excipient amount and its physicochemical properties (e.g., particle size distribution, substitution degree of polymer) based on an enhanced knowledge over a wider range of material attributes. The applicant should justify the rationale for establishing the design space with respect to quality attributes such as bioequivalence, stability, manufacturing robustness etc. Formulation adjustment within the design space
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depending on material attributes does not need a submission in a regulatory
postapproval change. (Approved June 2009)
Q8: Does a set of proven acceptable ranges alone constitute a design space?
A8: No, a combination of proven acceptable ranges (PARs) developed from univariate experimentation does not constitute a design space (see Q8(R2) Annex, section
II.D.5 (2.4.5)). Proven acceptable ranges from only univariate experimentation may lack an understanding of interactions between the process parameters and/or material attributes. However proven acceptable ranges continue to be acceptable from the regulatory perspective but are not considered a design space (see ICH Q8(R2) Annex, section II.D.5 (2.4.5)).
The applicant may elect to use proven acceptable ranges or design space for
different aspects of the manufacturing process. (Approved June 2009)
Q9: Should the outer limits of the design space be evaluated during process validation studies at the commercial scale?
A9: No. There is no need to run the qualification batches at the outer limits of the design space during process validation studies at commercial scale. The design space should be sufficiently explored earlier during development studies (for scale-up, see also section II.B.1 Design Space (2.1), Q2; for lifecycle approach, see section II.A For General Clarification (1.1), Q3). (Approved November 2010)
2. Real-Time Release Testing (2.2)
Q1: How is batch release affected by employing real-time release testing?
A1: Batch release is the final decision to release the product to the market regardless of whether RTR testing or end-product testing is employed. End-product testing involves performance of specific analytical procedures on a defined sample size of the final product after completion of all processing for a given batch of that product. Results of real-time release testing are handled in the same manner as end-product testing results in the batch release decision. Batch release involves an independent review of batch conformance to predefined criteria through review of testing results and manufacturing records together with appropriate good manufacturing practice (GMP) compliance and quality system, regardless of which approach is used. (Approved April 2009)
Q2: Does real-time release testing mean elimination of end-product testing?
A2: Real-time release testing does not necessarily eliminate all end-product testing. For example, an applicant can propose RTR testing for some attributes only or not all. If all critical quality attributes (CQAs) (relevant for real-time release testing)
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are assured by in-process monitoring of parameters and/or testing of materials, then end-product testing might not be needed for batch release. Some product testing will be expected for certain regulatory processes such as stability studies or regional requirements. (Approved April 2009)
Q3: Is a product specification still necessary in the case of RTR testing?
A3: Yes, product specifications (see ICH Q6A and Q6B) still need to be established and met, when tested.3 (Approved April 2009)
Q4: When using RTR testing, is there a need for stability test methods?
A4: Even where RTR testing is applied, a stability monitoring protocol that uses stability indicating methods is required4 for all products regardless of the means of release testing (see ICH Q1A and ICH Q5C). (Approved April 2009)
Q5: What is the relationship between control strategy and RTR testing?
A5: RTR testing, if utilized, is an element of the control strategy in which tests and/or monitoring can be performed as in-process testing (in-line, on-line, at-line) rather than tested on the end product. (Approved April 2009)
Q6: Do traditional sampling approaches apply to RTR testing?
A6: No, traditional sampling plans for in-process and end-product testing involve a discrete sample size that represents the minimal sampling expectations. Generally, the use of RTR testing will include more extensive on-line/in-line measurement. A scientifically sound sampling approach should be developed, justified, and implemented. (Approved April 2009)
Q7: If RTR testing results fail or trending toward failure, can end-product testing be used to release the batch?
A7: No, in principle the RTR testing results should be routinely used for the batch release decisions and not be substituted by end-product testing. Any failure should be investigated and trending should be followed up appropriately. However, batch release decisions should be made based on the results of the investigations. In the case of failure of the testing equipment, please refer to the previous question. The batch release decision should comply with the content of the marketing authorization and GMP compliance. (Approved April 2009)
3 See 21 CFR 314.50(d)(1) and 21 CFR 211.165. 4 21 CFR 314.50(d)(1).
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Q8: What is the relationship between in-process testing and RTR testing?
A8: In-process testing includes any testing that occurs during the manufacturing process of drug substance and/or finished product. Real-time release testing includes those in-process tests that have a direct impact on the decision for batch release through evaluation of critical quality attributes. (Approved June 2009)
Q9: What is the difference between “real time release” and “real-time release testing”?
A9: The definition of real-time release testing in Q8(R2) is “the ability to evaluate and ensure the acceptable quality of in-process and/or final product based on process data, which typically includes a valid combination of measured material attributes and process controls.”
The term real time release in the Q8(R2), step 2 document was revised to “realtime release testing” in the final Q8(R2) Annex to fit the definition more accurately and thus avoid confusion with batch release. (Approved June 2009)
Q10: Can surrogate measurement be used for RTR testing?
A10: Yes, RTR testing can be based on measurement of a surrogate (e.g., process parameter, material attribute) that has been demonstrated to correlate with an in-process or end-product specification (see ICH Q8(R2); Annex, section II.E (2.5)). (Approved June 2009)
Q11: What is the relationship between RTR testing and parametric release?
A11: Parametric release is one type of RTR testing. Parametric release is based on process data (e.g., temperature, pressure, time for terminal sterilization, physicochemical indicator) rather than the testing of material and/or a sample for a specific attribute. (Approved October 2009)
3. Control Strategy (2.3)
Refer to the definition of control strategy provided in the ICH Q10 glossary:
A planned set of controls, derived from current product and process understanding that assures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control.
Q1: What is the difference in a control strategy for products developed using the minimal approach vs. “quality-by-design” approach?
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A1: Control strategies are expected irrespective of the development approach. Control strategy includes different types of control proposed by the applicant to assure product quality (ICH Q10, section IV.B.1 (3.2.1)), such as in-process testing and end-product testing. For products developed following the minimal approach, the control strategy is usually derived empirically and typically relies more on discrete sampling and end-product testing. Under QbD, the control strategy is derived using a systematic science and risk-based approach. Testing, monitoring, or controlling is often shifted earlier into the process and conducted in-line, online, or at-line testing. (Approved April 2009)
Q2: Are GMP requirements different for batch release under QbD?
A2: No, the same GMP requirements apply for batch release under minimal and QbD approaches. (Approved April 2009)
Q3: What is the relationship between a design space and a control strategy?
A3: A control strategy is required for all products.5 If a design space is developed and approved, the control strategy (see ICH Q8(R2), Annex, section IV (4)) provides the mechanism to ensure that the manufacturing process is maintained within the boundaries described by the design space. (Approved April 2009)
Q4: What approaches can be taken in the event of on-line/in-line/at-line testing or monitoring equipment breakdown?
A4: The control strategy provided in the application should include a proposal for use of alternative testing or monitoring approaches in cases of equipment failure. The alternative approach could involve use of end-product testing or other options, while maintaining an acceptable level of quality. Testing or monitoring equipment breakdown should be managed in the context of a deviation under the quality system and can be covered by GMP inspection. (Approved June 2009)
Q5: Are product specifications different for minimal versus QbD approaches?
A5: In principle no, product specifications are the same for minimal and QbD approaches. For a QbD approach, the control strategy can facilitate achieving the end product specifications via real time release testing approaches (see ICH Q8(R2) Annex, appendix 1). Product must meet specification, when tested.6 (Approved October 2009)
5 21 CFR 314.50(d)(1). 6 21 CFR 211.165.
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C. Pharmaceutical Quality System (3)
Q1: What are the benefits of implementing a pharmaceutical quality system (PQS) (in accordance with ICH Q10)?
A1: The benefits are:
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Facilitated robustness of the manufacturing process, through facilitation of continual improvement through science and risk-based postapproval change processes
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Consistency in the global pharmaceutical environment across regions
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Enable transparency of systems, processes, and organizational and management responsibility
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Clearer understanding of the application of a quality system throughout product lifecycle
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Further reducing risk of product failure and incidence of complaints and recalls, thereby providing greater assurance of pharmaceutical product consistency and availability (supply) to the patient
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Better process performance
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Opportunity to increase understanding between industry and regulators and more optimal use of industry and regulatory resources; enhance manufacturer’s and regulators’ confidence in product quality
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Increased compliance with GMPs, which builds confidence in the regulators
and may result in shorter inspections
(Approved April 2009)
Q2: How does a company demonstrate implementation of PQS in accordance with ICH Q10?
A2: When implemented, a company will demonstrate the use of an effective PQS through its documentation (e.g., policies, standards), its processes, its training/qualification, its management, its continual improvement efforts, and its performance against pre-defined key performance indicators (see ICH Q10 glossary on performance indicator).
A mechanism should be established to demonstrate at a site how the PQS operates across the product lifecycle, in an easily understandable way for management, staff, and regulatory inspectors, e.g., a quality manual, documentation, flowcharts, procedures. Companies can implement a program in which the PQS is routinely audited in-house (i.e., internal audit program) to ensure that the system is functioning at a high level. (Approved April 2009)
Q3: Is it necessary to describe the PQS in a regulatory submission?
A3: No, however relevant elements of the PQS (such as quality monitoring system, change control, and deviation management) can be referenced as part of the control strategy as supporting information. (Approved April 2009)
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Q4: Will there be certification that the PQS is in accordance with ICH Q10?
A4: No. There will not be a specific ICH Q10 certification program. (Approved April 2009)
Q5: How should the implementation of the design space be evaluated during inspection of the manufacturing site?
A5: Inspection should verify/assess that manufacturing operations are appropriately carried out within the design space. The inspector in collaboration with the assessor, where appropriate, should also verify successful manufacturing operations under the design space and that movement within the design space is managed within the company’s change management system (see ICH Q10, section IV. B.3 (3.2), Table III). (Approved April 2009)
Q6: What should be done if manufacturing operations run inadvertently outside of the design space?
A6: This should be handled as a deviation under GMP. For example, unplanned “oneoff” excursions occurring as a result of unexpected events, such as operator error or equipment failure, would be investigated, documented, and dealt with as a deviation in the usual way. The results of the investigation could contribute to the process knowledge, preventive actions, and continual improvement of the product. (Approved April 2009)
Q7: What information and documentation of the development studies should be available at a manufacturing site?
A7: Pharmaceutical development information (e.g., supporting information on design space, chemometric model, risk management) is available at the development site. Pharmaceutical development information that is useful to ensure the understanding of the basis for the manufacturing process and control strategy, including the rationale for selection of critical process parameters and critical quality attributes, should be available at the manufacturing site.
Scientific collaboration and knowledge sharing between pharmaceutical development and manufacturing is essential to ensure the successful transfer to production. (Approved June 2009)
Q8: Can process parameters be adjusted throughout the product lifecycle?
A8: Process parameters are studied and selected during pharmaceutical development and monitored during commercial manufacturing. Knowledge gained could be utilized for adjustment of the parameters as part of continual improvement of the process throughout the lifecycle of the drug product (see ICH Q10, section IV (3)). (Approved June 2009)
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D. Impact of New ICH Quality Guidance on GMP Inspection Practices (4)
Q1: How will product-related inspections differ in an ICH Q8, Q9 and Q10 environment?
A1: In the case of product-related inspection (in particular, preauthorization) depending on the complexity of the product and/or process, greater collaboration between inspectors and assessors could be helpful (for example, for the assessment of development data). The inspection would normally occur at the proposed commercial manufacturing site, and there is likely to be greater focus on enhanced process understanding and understanding relationships, e.g., critical quality attributes (CQAs), critical process parameters (CPPs). The inspection might also focus on the application and implementation of quality risk management principles, as supported by the pharmaceutical quality system (PQS). (Approved April 2009)
Q2: How will system-related inspections differ in an ICH Q8, Q9, and Q10 environment?
A2: The inspection process will remain similar. However, upon the implementation of ICH Q8, Q9, and Q10, inspections will have greater focus on (but not only focus on) how the PQS facilitates the use of e.g., quality risk management methods, implementation of design space, and change management (see ICH Q10). (Approved April 2009)
Q3: How is control strategy approved in the application and evaluated during inspection?
A3: Elements of control strategy submitted in the application will be reviewed and approved by the regulatory agency. However, additional elements are subject to inspection (as described in Q10). (Approved October 2009)
E. Knowledge Management (5)
Q1: How has the implementation of ICH Q8, Q9, and Q10 changed the significance and use of knowledge management?
A1: Q10 defines knowledge management as: “Systematic approach to acquiring, analyzing, storing, and disseminating information related to products, manufacturing processes and components.”
Knowledge management is not a system; it enables the implementation of the concepts described in ICH Q8, Q9 and Q10.
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Knowledge management is not a new concept. It is always important regardless of the development approach. Q10 highlights knowledge management because it is expected that more complex information generated by appropriate approaches (e.g., QbD, process analytical technology (PAT), real-time data generation, and control monitoring systems) should be better captured, managed, and shared during product life-cycle.
In conjunction with quality risk management, knowledge management can facilitate the use of concepts such as prior knowledge (including from other similar products), development of design space, control strategy, technology transfer, and continual improvement across the product life cycle. (Approved April 2009)
Q2: Does Q10 suggest an ideal way to manage knowledge?
A2: No. Q10 provides a framework and does not prescribe how to implement knowledge management. Each company decides how to manage knowledge, including the depth and extent of information assessment based on its specific needs. (Approved April 2009)
Q3: What are potential sources of information for knowledge management?
A3: Some examples of knowledge sources are:
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Prior knowledge based on experience obtained from similar processes (internal knowledge, industry scientific and technical publications) and published information (external knowledge: literature and peer-reviewed publications)
•
Pharmaceutical development studies
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Mechanism of action
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Structure/function relationships
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Technology transfer activities
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Process validation studies
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Manufacturing experience, e.g.,
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Internal and vendor audits
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Raw material testing data
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Innovation
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Continual improvement
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Change management activities
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Stability reports
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Product quality reviews/annual product reviews
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Complaint reports
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Adverse event reports (patient safety)
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Deviation reports, recall Information
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Technical investigations and/or CAPA reports
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Suppliers and contractors
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Product history and /or manufacturing history
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Ongoing manufacturing processes information (e.g., trends)
Information from the above can be sourced and shared across a site or company, between companies and suppliers/contractors, products, and across different disciplines (e.g., development, manufacturing, engineering, quality units). (Approved April 2009)
Q4: Is a specific dedicated, computerized information management system required for the implementation of knowledge management with respect to ICH Q8, Q9, and Q10?
A4: No, but such computerized information management systems can be invaluable in capturing, managing, assessing, and sharing complex data and information. (Approved April 2009)
Q5: Will regulatory agencies expect to see a formal knowledge management approach during inspections?
A5: No. There is no added regulatory requirement for a formal knowledge management system. However, it is expected that knowledge from different processes and systems will be appropriately utilized.
Note: “formal” means: it is a structured approach using a recognized methodology or information technology (IT) tool, executing and documenting something in a transparent and detailed manner. (Approved June 2009)
F. Software Solutions (6)
Q1: With the rapid growth of the new science and risk-based quality paradigm coupled with the IWG efforts to facilitate globally consistent implementation of Q8, Q9, and Q10, a number of commercial vendors are now offering products that are being marketed as “ICH compliant solutions” or ICH Q8, 9, and 10 Implementation software, etc. Is it necessary for a pharmaceutical firm to purchase these products to achieve a successful implementation of these ICH guidances within their companies?
A1: No. The ICH Implementation Working Group has not endorsed any commercial products and does not intend to do so. ICH is not a regulatory agency with reviewing authority and thus does not have a role in determining or defining “ICH compliance” for any commercial products. While there will likely be a continuous proliferation of new products targeting the implementation of these ICH guidances, firms should carry out their own evaluation of these products relative to their business needs. (Approved April 2009)
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