quality by design for andas: immediate-release dosage forms · for andas: immediate-release dosage...

Quality by Design

for ANDAs: Immediate-Release

Dosage Forms

An Industry-FDA Perspective

FDA/GPhA Workshop Draft Example Product Development Report

May 4-5, 2010

Example QbD Tablet Module 3 Quality 3.2.P.2 Pharmaceutical Development

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January 2010

Quality by Design: An Industry/FDA Perspective

What is Quality by Design (QbD)? It is a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on the sound science and quality risk management. This approach to development will allow sponsors to present the information gained through development as well as utilizing prior knowledge in order to demonstrate and document that they understand both their product and process. The objective of this initiative is to ensure that industry has identified the critical material attributes and critical process parameters through prior knowledge, experimentation and risk assessment. It is FDA’s expectation that sponsors will determine the functional relationships that link critical material attributes and critical process parameters to the product’s critical quality attributes. The goal is for sponsors to envision commercialization of drug product at the start of development and continue to keep that objective in mind as they move through the development process. This is also referred to as Quality Target Product Profile (QTPP). The QTPP forms the basis of design for the development of the drug product. The QTPP could include critical and non-critical elements. When defining QTPP sponsors should think about the development goal. A sub-set of the QTPP is the Critical Quality Attributes (CQAs) which form the basis for the product specification. A Critical Material Attribute (CMA) is a physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired API, excipient, or in-process material quality. A Critical Quality Attribute (CQA) is a physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired drug product quality. A Critical Process Parameter (CPP) is a process parameter whose variability has an impact on a CMA of the in-process material or CQA and therefore should be monitored or controlled to ensure the process produces the desired quality of the finished drug product. Why is QbD important? QbD will increase transparency of the sponsor’s understanding of the control strategy for the drug product that it seeks to obtain approval and ultimately commercialize. When the sponsor can demonstrate process and product understanding then it will assist FDA in facilitating the CMC review and ultimately decrease the number of


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deficiencies and review time. In addition, with this added knowledge base, the scale-up, validation and commercialization will be transparent, rationale and predictable.


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How do sponsors document/incorporate the QbD information? All QbD information should be captured in the Pharmaceutical Development Report which is provided in Section 3.2.P.2 of CTD submissions. The goal of pharmaceutical development reports is to identify the critical material attributes and critical process parameters through prior knowledge, experimentation and risk assessment. It should also include the functional relationships that link critical material attributes and critical process parameters to product CQAs. Sponsors should use their enhanced product and process understanding in combination with quality risk management to establish an appropriate control strategy. The Pharmaceutical Development report should include the following sections: Analysis of the Reference Product – A review/summary/highlight of the reference product should be presented. This would include a review of the RLD product label, USP and/or Pharm Forum compendia information, a review of the literature regarding the analytical profiles of API, Pubmed et. al., preliminary experiments conducted on the RLD, review of the inactive ingredients with the IIG, FDA dissolution web site and guidance’s, review of SBA on the RLD. Quality Target Product Profile (QTPP) of the sponsor proposed ANDA drug product. This section provides the basis of design that the sponsor is using to develop the drug product. When defining the QTPP the sponsor should think about the development goal. An example of a tablet that could be used to outline the profile components is provided below. Please note that this table is not all inclusive and would change based on the critical and noncritical elements determined. Each table should be product specific.


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2.1 Component of Drug product 2.1.1. Drug Substance: A thorough knowledge and understanding of the physiochemical, and biological properties should be included (i.e., solubility, water content, particle size, crystal properties, impurities, stability, permeability and biological activity). It is important that the sponsor understands how these properties can influence the performance of the drug product and manufacturing process. In addition the compatibility of the drug substance with excipients used in the drug product should be evaluated. For products that have multiple drug substances compatibility of the drug substances with each other should also be evaluated. Those drug substance characteristics that are identified as Critical Material Attributes (CMAs) need to be discussed and a rationale for why the proposed limits/specificaitons were established needs to be given. 2.1.2 Excipients This section should include the “why, what and how” of excipients. Why were they chosen, what do they do and how do they influence the drug product performance and the manufacturability. Compatibility of excipients with other excipients where relevant, should be established. Demonstration of how their functionality continues throughout the drug product shelf life should be included. Prior knowledge and appropriate development data regarding excipients compatibility, stability, and performance should be provided and discussed in detail. 2.2. Drug Product A summary describing the development of the formulation which includes the Critical Quality Attributes (CQAs) in detail should be provided. Information obtained through prior knowledge or formal experience should be discussed. This section should highlight the evolution of the formulation design from initial concept up to the final design. This should include what properties of the drug substance, excipients, container closure system, and dosing device if applicable, manufacturing process and stability attributes were considered when making a final decision on how to develop the proposed drug product. Data from exicipient range studies, pilot or pivotal bioequivalence studies, in-vitro studies (dissolution) that were used to either confirm the drug product formulation or were used to modify the drug product formulation should be clearly described and a rationale for the change provided.


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Any special design features of the drug product (e.g., tablet score, overfill, anti-counterfeiting measures as it affects the drug product) should be identified and a rationale provided for their use. The sponsor should make attempts to establish in vitro/in vivo relationships and the results of those studies should be included and summarized. A successful relationship can assist in the selection of appropriate dissolution acceptance criteria and can potentially reduce the need for further bioequivalence studies following changes to the product or its manufacturing process. 2.3 Process Development The development of the manufacturing process should use a systematic approach for determining the formulation and manufacturing process. This can occur by utilizing prior knowledge and experience with similar dosage forms or by utilizing formal design of experiments and studies. It is important that sponsors understand the impact that process parameters have on the in process material attributes and drug product CQAs. This can be done by conducting risk analysis and developing mitigation strategies. Sponsors should determine the critical process parameters and their acceptable operating ranges. 2.3.1 Identification of the Critical Process parameters This section should include a discussion regarding what process testing and/or process studies were done in order to obtain knowledge and understanding of the manufacturing process. Some examples are provided but not limited to the following types of testing that should be considered:

• Identification and rationale for equipment and process • Order of ingredient addition • Blend time studies • Hold time studies • Milling conditions • Temperature studies • Granulation studies • Lubrication sensitivity • Compression or encapsulation trials • Performance test results • Process optimization/robustness studies • Container closure system impact • Compatibility of the drug product with reconstitution diluents (if applicable)

By conducting the studies outlined above, the process parameter ranges and their impact on the finished product CQAs are collected, analyzed and summarized in order to gain an understanding of the proposed product design space.


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The knowledge gained from these process development studies can be used to justify the drug product specification as well as to identify the manufacturing process steps that are considered critical and will require monitoring and control. In addition, these studies can also rule out those steps that are not critical to the manufacturing process and therefore could be changed with minimal impact on the product quality. 2.3.2 Scale Up In this section of the pharmaceutical development report the results of batches manufactured at various scales and the impact of process parameter changes should be presented and discussed. Significant differences between the manufacturing processes used to produce registration/exhibit batches, primary stability studies verses commercial scale should be outlined. These discussions should summarize the differences on the performance, manufacturability, and quality of the product. The information should be presented in a way that facilitates comparison of the processes and the corresponding batch analyses information. If scale up has not occurred then it is critical that an analysis be done of what the potential scale up parameters should be based on prior knowledge and the identified CQA and CPP for each unit of operation. 2.3.3 Control Strategy The control strategy is the combination of input material controls, process controls and monitoring, design spaces around individual or multiple unit operations, and final product specifications used to ensure consistent quality. Testing, monitoring or controlling is often shifted earlier into the process and conducted in-line, on-line or at-line testing. Under QbD the control strategy is derived using a systematic science and risk based approach.


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Introduction to the Example

This is an example pharmaceutical development report illustrating how ANDA sponsors can move toward implementation of quality by design. The example builds on the Conformia ACE case study by treating that product as the reference product for the development of a generic product. The example is in two parts: (1) a detailed pharmaceutical development report and (2) a quality overall summary (QOS) that includes answers to the questions in OGD’s question-based review process. The purpose of the example is to illustrate the types of pharmaceutical development studies ANDA sponsor may use as they implement QbD in their development process and promote discussion on how OGD would use this information in review. Potential questions for discussion based on this example include:

• Is this amount of effort in pre-submission pharmaceutical development a reasonable expectation for ANDA sponsors?

• What are the benefits for the ANDA sponsor from the QbD approach in this example? • What are the benefits to the OGD reviewer and the consumer of the QbD approach in

this example? • Does OGD’s current question-based review effectively capture how ANDA sponsors

would use QbD? • How does QbD implemented by an ANDA sponsor compare to the vision of QbD in the

ACE case study? • Is the scope and justification of the quality target product profile appropriate? • Was the use of risk assessment and risk mitigation by the ANDA sponsor effective?

How should an OGD reviewer evaluate the sponsor’s risk assessment? • Did the ANDA sponsor’s control strategy provide assurance that the product will

consistently meet the quality target product profile? • Was the identification of critical quality attributes and critical process parameters

correct? • Although the sponsor conducted several multivariate experiments, this example

application did not claim a design space in the final control strategy. What additional information (better process models or commercial scale experimental data) would be needed to justify a design space?

Although we have tried to make the example as realistic as possible, the development of a real product may differ from this example. The example is for illustrative purposes and depending on a firms experience and prior knowledge the degree of experiments for a particular product may vary. The impact of experience and prior knowledge should be explained in the submission. The risk assessment process is one avenue for this explanation. At many places in this example alternative pharmaceutical development approaches would also be appropriate. This example illustrates one of many possible approaches. Notes to the reader are included in italics at the beginning of many sections.


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Pharmaceutical Development Report Example QbD for Generic Drugs

Draft January 18, 2010

Table of Contents 1.1 Overview................................................................................................................................. 10 1.2 Analysis of the Reference Product.......................................................................................... 12 1.3 QTPP for ANDA Product ....................................................................................................... 15 2.1 Components of Drug Product ................................................................................................. 16

2.1.1 Drug Substance 16 2.1.1.1 Drug Substance Solubility ............................................................................................17 2.1.1.2 Drug Substance Polymorphism.....................................................................................17 2.1.1.3 Drug Substance Stability...............................................................................................18 2.1.1.4 Drug Substance Particle Size ........................................................................................19

2.1.2 Excipients 21 2.1.2.1 Excipient Compatibility Studies ...................................................................................22

2.2 Drug Product........................................................................................................................... 23 2.2.1 Formulation Development 23

2.2.1.1 Development PK Study 1001........................................................................................25 2.2.1.2 Excipient Grade Selection.............................................................................................28 2.2.1.3 Formulation Risk Assessment.......................................................................................29 2.2.1.4 Formulation Study #1 Formulation Optimization.........................................................30 2.2.1.5 Formulation Study #2 Magnesium Stearate..................................................................33

2.2.2 Conclusions of Formulation Development 34 2.3 Process Development.............................................................................................................. 35

2.3.1 Identification of Critical Process Parameters 38 2.3.1.1 Pre-Granulation Blending .............................................................................................38 2.3.1.2 Roller Compaction and Milling ....................................................................................44 2.3.1.3 Granule Lubrication ......................................................................................................49 2.3.1.4 Tablet Compression ......................................................................................................49

2.3.2 Scale Up 56 2.3.3 Control Strategy 58

2.3.3.1 Control Strategy for Blending.......................................................................................61 2.3.3.2 Control Strategy for Roller Compaction and Milling ...................................................61 2.3.3.3 Control Strategy for Lubrication...................................................................................61 2.3.3.4 Control Strategy for Tablet Compression .....................................................................61 2.3.3.5 Reduced Release Testing ..............................................................................................61

3.1 Development Conclusions ...................................................................................................... 61


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1.1 Overview First, we defined the Quality Target Product Profile (QTPP) based on the RLD label and our characterization of the RLD. We developed a dissolution method that we believe is the best target for pharmaceutical development. Acetriptan with different particle sizes was obtained from the same supplier. Our characterization of the drug substance concluded that

• Acetriptan particle size had a significant effect on dissolution • Degradation of acetriptan is a function of temperature • Acetriptan is compatible with excipients proposed for use in the product after a potential

interaction with magnesium stearate was investigated and minimized • Acetriptan had particle characteristics (shape, surface charge, agglomeration) that lead

to poor mixing and flow. Based on this characterization, we decide to use a formulation with similar components to the RLD formulation. This formulation was evaluated in a pilot PK study to establish an in vitro dissolution method that could confidently guide further development. We did not use intergranular magnesium stearate since it increased the potential for degradation. Formulation development consisted of studies that characterized

• The robustness of the proposed formulation to variation in the composition and drug substance particle size

• The effect of magnesium stearate level. The sensitivity of product quality to variation in excipient particle size was also considered in formulation development. Specific grades of excipients were selected and additional control of excipient particle size was added.

We decided to use a roller compaction process (Figure 1) to manufacture the drug product since the drug substance caused significant problems in blend uniformity after dry mixing that were mitigated by the use of roller compaction. The heat sensitivity of acetriptan ruled out drying after an aqueous wet granulation and environmental cost considerations eliminated wet granulation with organic solvents. Based on a risk assessment of the process to identify potentially critical variables, we conducted the following process development studies:

• A DOE study of blending time and input material attributes (DS and excipient PSD) with an endpoint of uniformity. This study also established the use of PAT method for the uniformity endpoint.

• A study establishing the process parameters for roller compaction and providing a basis for future scale up

• A study to establish the robustness of granule lubrication time • A study to establish process parameters for tableting


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• A study to evaluate whether material properties after blending and roller compaction would lead to appropriate tableting.

We used the information gained in development to prepare a control strategy to ensure consistent product quality and mitigate the risks identified in our risk assessment process.

Table 1 Development Presented in Chronological Order Time Study Scale Section

Q1 200x Evaluation of RLD 1.2 Q1 200x Evaluate DS properties 2.1.1 Q1 200x DS/Excipient compatibility 2.1.2.1 Q1 200x In vitro dissolution method development using DS with

different particle size 2.1.1.4.1

Q1 200x Attempted direct compression of RLD formulation Lab (500 g)

2.1.1.4.2

Q1 200x Selection of roller compaction 2.3 Q2 200x Development of laboratory scale roller compaction

process Lab (500 g)

2.3

Q2 200x Selection of formulation for pilot PK study 2.2.1 (Table 13)

Q2 200x PK Study 1001: Pilot formulation with variation of DS particle size

Lab (500 g)

2.2.1.1

Q2 200x Dissolution study on drug product formulation used in PK study

Lab (500 g)

2.2.1.1

Q2 200x Evaluation of polymorphic form via XRPD Lab (500 g)

2.1.1.2

Q2 200x Formulation Dev-1: Variation of Lactose/MCC/CCS and particle size

Lab (500 g)

2.2.1.4

Q2 200x Formulation Dev-2: Attempted removal of magnesium stearate

Lab (500 g)

2.2.1.5

Q2 200x ProcDev-1: Critical process parameters for blending Pilot (1.5 kg)

2.3.1.1

Q3 200x ProcDev-2: Critical process parameters for roller compaction

Pilot (1.5 kg)

2.3.1.2

Q3 200x ProcDev-2a: Critical process parameters for lubrication Pilot (1.5 kg)

2.3.1.3

Q3 200x ProcDev-3: Tablet compression parameters Pilot (1.5 kg)

2.3.1.4.2

Q3 200x ProcDev-4: Effect of material variation on compression Pilot (1.5 kg)

2.3.1.4.3

Q3 200x Scale up to exhibit batch size 2.3.2 Q3 200x BioStudy Exhibit

(50 kg)


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Figure 1 Overview of Manufacturing Process

1.2 Analysis of the Reference Product RLD Dissolution and Selection of Product Development Dissolution Method

Note to Reader: A pharmaceutical development report should document the selection of the dissolution method that is used in pharmaceutical development. This method (or methods) may be different from the FDA recommended method and different from the quality control method used for release testing. As acetriptan is a BCS Class II compound displaying poor aqueous solubility (less than 0.015 mg/mL) across the physiological pH range, development of a dissolution method that can act as the best available predictor of equivalent pharmacokinetics to the RLD was important to allow assessment of acetriptan tablets manufactured during development. The objective was a dissolution test method that provided the best available estimate of comparative performance with the RLD.


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Development began with the quality control dissolution method recommended by FDA for this product: (0.1 N HCl with 2.0% w/v SLS). Because the target is an immediate release product with a rapid onset of action (Tmax for the RLD is 1.3 hours), dissolution in the stomach and absorption in the upper small intestine are expected. This suggested the use of dissolution media with low pH. Because of acetriptan’s low solubility in water, the solubility of acetriptan in biorelevant media and aqueous media with varying surfactant concentrations was measured (see Table 6). Figure 2 shows the dissolution of the RLD with different surfactant concentrations. The solubility of acetriptan with surfactant concentration of 1-2% is similar to its solubility in biorelevant media. To select a dissolution method to use in product development, Figure 3 shows an evaluation of the ability of different surfactant concentrations to discriminate between different drug substance particle sizes. The dissolution method selected for product development uses 0.1 N HCl in a dissolution apparatus equipped with paddles (speed 75 rpm) and a volume of 900 ml of SLS (1.0% w/v) maintained at a temperature of 37°C, followed by UV spectroscopy at a wavelength of 282 nm. Dissolution in 1.0% SLS is robust with respect to paddle speed (similar at 50, 75, and 100 rpm) and media pH (similar in 0.1 N HCl, pH 4.5 buffer and pH 6.8 buffer). At a paddle speed of 75 rpm, the 1.0% w/v SLS medium is capable of reproducibly discriminating between tablets manufactured by variation of the API particle size. This data was collected later in formulation development. The data also demonstrated that the proposed method is suitable for use as a routine control test and is more sensitive than the FDA recommended method. Pilot PK study 1001 suggested that drug product manufactured with particle sizes (d90) of 45 and 30 µm would both be bioequivalent to the RLD.

Figure 2 Dissolution of the RLD as a function of surfactant in 0.1N HCl


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Figure 3 Dissolution of acetriptan drug substance as a function of particle size in 0.1N HCl and 1% SLS (left) and 2% SLS (right) compared to the dissolution of the RLD drug product.

RLD Characterization Characterization included determination of the RLD composition and characterization of the impurity level for ACE12345 (a known degradation product). The RLD drug product is a uniform tablet with no cosmetic coating and no scoring. The tablet needs to be swallowed “as is” without any intervention. Thus the proposed product will also be a uniform tablet with no cosmetic coat and no scoring.


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RLD Composition The initial RLD characterization provided the overall composition in Table 2.

Table 2 Characterization of the RLD composition Ingredient Function Weight/tablet % (w/w)

Acetriptan, USP Active 20.00 mg 10 Lactose Monohydrate, NF Filler 64-86 mg 32 – 43% Microcrystalline Cellulose, NF Filler 72 – 92 mg 36 – 46% Croscarmellose Sodium, NF Disintegrant 2 – 10 mg 1- 5% Magnesium Stearate, NF Lubricant 2 – 6 mg 1-3% Talc, NF Glidant/Lubricant 1-10 mg 0.5-5% Total Weight 200.0 mg

The ranges for each excipient are based on reverse engineering on the RLD, prior knowledge of the excipient and the level of IIG for oral solid dosage form.

1.3 QTPP for ANDA Product

Note to Reader: The Quality Target Product Profile (QTPP) is described in ICH Q8 and is an essential element of a quality by design approach. For ANDAs, the target should be defined early in development based on the properties of the drug substance, characterization of the RLD product and consideration of the RLD label and intended patient population.

The QTPP includes all product attributes that are needed to ensure equivalent safety and efficacy to the RLD. This example is for a simple IR tablet; other products would include additional attributes in the QTPP. An ODT would include disintegration time. A scored tablet would include properties of split tablets. Tablet weight may be part of the profile if it is known early in development, perhaps because of a desire for multiple strengths with proportional formulations. In other cases, like this example, there is not a desire target weight and formulation development is not constrained.

Some of the elements of the QTPP may change during pharmaceutical development as more is learned about the product. The evolution should be documented in the development report. At the end of development the result is not a final QTPP. The result of development is an acceptable control strategy and regulatory specification. For example, the final impurity and residual solvent specifications may depend on the properties of excipients used in the formulation.

The critical elements, derived from the QTPP and tracked closely in development, are identified as critical quality attributes.

An analysis of the reference product and its label identified a quality target product profile (Table 3) that included rapid dissolution and other aspects of product quality and equivalence. The maximum daily dose in the label is 40 mg/day.


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Table 3 Quality Target Product Profile Profile

Component Target Justification

Dosage Form Tablet ANDA needs same dosage form as RLD

Dosage Design Immediate release tablet Immediate release design needed to meet label claims

Strength 20 mg Require to match RLD

Pharmacokinetics Immediate release enabling Tmax in 2 hours or less. AUC and Cmax match RLD.

AUC and Cmax need for BE requirement. Tmax needed because indication is for immediate onset of action.

Identity Positive for acetriptan Needed for clinical effectiveness and safety

Assay 100% of label claim Needed for clinical effectiveness Impurities ACE12345 NMT 0.5%,

Any other impurity NMT 0.2%, Total other impurities NMT 1%

ACE12345 is common degradant, its level is above the ICH qualification threshold and is qualified by RLD characterization

CU AV < 15 Targeted for consistent clinical effectiveness

Friability NMT 1.0% Needed for patient acceptability

Dissolution NLT 75% at 30 mins, 0.1N HCl , 1% SLS, 75 rpm

Needed to ensure rapid onset and equivalent bioavailability

Microbiology If testing required, meets USP criteria

Stability 24 month shelf life Needed for commercial reasons

From the QTPP, the following drug product Critical Quality Attributes (CQA) were identified for use in risk assessment. The criteria for inclusion in this list of CQA were that these attributes had the potential to be altered by process parameters or formulation variables.

Table 4 Drug Product CQA

DP CQA Justification Assay Needed for clinical effectiveness Impurity Needed to ensure safety CU Needed for clinical effectiveness Dissolution Needed for clinical effectiveness

2.1 Components of Drug Product

2.1.1 Drug Substance As a basis for pharmaceutical development, drug substance characterization was performed and included solubility, stability, flow properties and the effect of particle size on dissolution.


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Table 5 Potential Impact of API Attributes on Drug Product Attributes API Attribute DP CQA Particle

Size Polymorphism

Solid State Form Stability Solvent

Content Impurity Solubility

Assay Low Low Low Low Low Low Impurity Low Low High High High Low CU High Low Low Low Low Low Dissolution High High Low Low Low High

2.1.1.1 Drug Substance Solubility Note to Reader: The use of biorelevant media is an evolving area. The pharmaceutical development report should document all solubility information obtained. The aqueous solubility of acetriptan is low (0.015 mg/mL) and constant across the physiological pH range due to the lipophilic nature of the molecule. Calculated dose solubility volume: 20 mg (highest strength)/(0.015 mg/mL) = 1333 mL > 250 mL. Therefore, acetriptan is considered a low solubility drug according to the Biopharmaceutics Classification System (BCS).

Table 6 Solubility in biorelevant media and surfactant solutions Media Solubility Media Solubility

Biorelevant FaSSGF1 0.1 mg/mL 0.1 N HCl 0.015 mg/mL Biorelevant FaSSIF-V21 0.5 mg/mL pH 4.5 buffer 0.015 mg/mL

0.5% SLS 0.125 mg/mL pH 6.8 buffer 0.015 mg/mL 1.0% SLS 0.25 mg/mL 2.0% SLS 0.5 mg/mL

2.1.1.2 Drug Substance Polymorphism Note to Reader: Discussion of polymorphism begins here with identification of the potential forms and their impact on drug product performance and continue through development to ensure control of the form present in the drug product. In an actual pharmaceutical development for ANDA the actual literature references and the XRPD graphs are required to support the claims. Three different types of polymorphs were identified and reported in the literature for this drug substance. The three different forms were prepared in different crystallization conditions and different solvents were used. From this data, the solubility and the melting points are different for all three polymorphs. Solubility studies reported in the literature were conducted in water with surfactant. Based on the data obtained from the literature, polymorphic form III is the most stable form and has the highest melting point and it matches with the API supplied by our DMF holder. Our DMF holder provides the API in this polymorphic form consistently. Since it is the

1 Jantratid E, Janssen N, Reppas C, and Dressman JB. Dissolution Media Simulating Conditions in the Proximal Human Gastrointestinal Tract: An Update. Pharm Res 25:1663-7695, 2008


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most stable form, any phase transformation during the manufacturing process is not expected. The melting point is added in the API specification as a part of the control strategy. Though the API is supplied in its most stable form, we wanted to ensure that it remains the same during manufacturing process. Since the API is practically insoluble in water, the impact of change in polymorphic form on its in-vivo performance is not well understood. To evaluate whether processing conditions would affect the polymorphic form, the final drug product sampled from lab scale studies was evaluated by XRPD. The characteristic XRPD pictures of the API, MCC and lactose are given. From the XRPD figures it is evident that the characteristics 2 theta peaks of the API are retained in the final drug product. An advanced XRPD technique was utilized to detect the possible phase transition in the drug product since the level of drug substance was 10% in the drug product Since these three forms have distinctive melting points, we are including only the melting point in the API specification as an indicator for the polymorphic form. In the event we change our API supplier, we will also evaluate the polymorphic form of the API with additional techniques, such as XRPD, and include in our supplement.

2.1.1.3 Drug Substance Stability Note to Reader: Since this example refers to a fictitious molecule the mechanism of degradation cannot as well described as it would be for a real molecule. In an actual pharmaceutical development, typically, a comprehensive understanding of the API molecule, functional groups, degradation mechanism, potential degradants, synthetic impurities, impact of residual solvents and catalysts on CMA of the API would be demonstrated. In addition, a mechanistic understanding of the potential interaction of API and its impurities with excipients and its impurities that would help foresee or predict the interactions between them during manufacturing and during shelf life of the drug product is recommended. The mechanistic understanding can potentially be supported by drug excipient interaction studies.

2.1.1.3.1 Degradation of Acetriptan This section combines information from literature, the DMF holder, and forced degradation studies. Stress testing (forced degradation) was carried out on acetriptan to evaluate its impurity profile. The testing included the effect of temperatures higher than that used for accelerated testing, humidity (e.g., 90% relative humidity or greater), oxidation, and photolysis on the drug substance. The specified stress conditions were intended to result in approximately 5–20% degradation (if possible) of the acetriptan or represent a reasonable maximum condition achievable for the API. The stressed samples were compared to the unstressed sample (control). Stress conditions and results are listed in the table below. The objective of this stress study was to further understand the possible degradation pathway of the drug substance related to the specified impurities. In addition, the results from some of the stress conditions may also serve as a reference for the impurities generated during any of the processing conditions of drug product manufacturing.


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Table 7 Drug Substance Stability Stress conditions Assay Method

(Test method 125 a) Impurity Method (Test method 41)

% Assay Observed Degradants Untreated 99% N/A Saturated Liquid Solution 0.1N HCl/70°C/24 h 96% RC2: 2% RC3: 1% 0.1N NaOH/70°C/24 h 97% RC2: 2% RC3: 1% 3% H2O2/60°C/2 h 86% RC2: 10% RC3: 1% Purified water/60°C/24 h 96% RC2: 2% RC3: 1% Solid State Material Expose to humidity (90% RH)/25°C/7 days

99% RC2: 0.1% RC3: 0.1%

Expose to humidity (90% RH)/40°C/ 7 days

99% RC2: 0.1% RC3: 0.1%

Expose to humidity (90% RH)/60°C/12 h

95% RC2: 3% % RC3: 0.2% RC4: 1%

UV light (short and long wave length) 7 days

95% RC2: 3% RC3: 1%

Dry heat /60°C /12 h 95% RC2: 4% RC4: 1% Dry heat /1050C/12 h 82% RC2: 4% RC4: 14%

RC2= ACE12345, RC3= RRT=0.68, RC4= RRT=0.79

In house HPLC methods #41 and #125 are used to determine assay and the impurities of acetriptan. Samples are analyzed by HPLC equipped with peak purity analyzer (PDA). Degradation peaks were well resolved from the peaks of interest. The peak purity of the major peak (acetriptan) and monitored degradants RC2 and RC3 are observed to be > 0.99. The RC2 impurity is formed due to oxidation and the RC3 is result of further oxidation. The peak purity angle was less than the peak purity threshold, indicating no interference. There was no interference of degradants with the main peak or the RC2 and RC3 impurity peaks. Based on the results, compound ACE12345 (RC2) and RC3 (RRT = 0.68) are found as the principal degradation products that form during stress studies. RC3 was not found at long-term stability conditions. Under dry heat RC4 formed due to decomposition of drug substance at 105 ºC. Conclusion: Heat is correlated with formation of impurities in solid state forms.

2.1.1.4 Drug Substance Particle Size Drug substance was obtained with four different size distributions. In the development report d90 is used to describe the drug substance particle size distribution.

Table 8 Drug Substance Lots Used in Development Property Lot #1 Lot #2 Lot #3 Lot #4 d90 60 µm 45 µm 30 µm 15 µm d50 50 µm 40 µm 20 µm 10 µm d10 10 µm 8 µm 6 µm 4 µm

2.1.1.4.1 Effect of Particle Size on Dissolution


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Note to Reader: Figure 4 characterized dissolution of raw drug substance. Depending on drug substance surface properties this may not always be a useful approach. The presence of surfactant may be needed to reduce the interfacial tension between water and the drug substance. Because the drug substance has low solubility, particle size in the drug product is potentially critical. Figure 4 shows that the dissolution of the drug substance is a strong function of the particle size. It was concluded that particle size of acetriptan in the drug product would be a significant factor in determining the overall dissolution rate.

Figure 4 Dissolution profiles in USP apparatus 2 at 75 rpm and pH 1.2 with 1% SLS for different particle size

(d90) of the drug substance compared to the RLD drug product. Conclusion: Drug substance particle size (d90) should be less than 45 µm to give dissolution that is faster or equal to the RLD.

2.1.1.4.2 Effect of Particle Size on Material Handling In this application, particle sizes of acetriptan are small (d90< 30 µm as shown in formulation study #1) in comparison to particle sizes of lactose and MCC. For this size range, acetriptan is a cohesive powder, in which the adhesive forces (mechanic, electrostatic, Van der Waals, and surface tension) between particles exceed the particle weight by at least an order of magnitude. Due to the small particle sizes and cohesivity of acetriptan powders, direct compression is found to be inappropriate by the following studies:

• The flowability study of API powders per USP<1174> (see Table 9) was conducted. It is found that the flow property of samples is poor. Poor material flow may produce excessive weight variability for tablets due to uneven distribution of the drug substance, uneven bulk density and eventually uneven filling of die cavities on a tablet press. This


21

rules out the use of a high load tablet and supported the decision to use a similar drug load as the RLD, which has a 10% drug load.

Table 9 Flow Related Properties of Acetriptan Drug Substance Property d90 15 µm d90 30 µm d90 45 µm d90 60 µm Bulk density 0.26 gm/cc 0.27 gm/cc 0.28 gm/cc 0.29 gm/cc Tapped density 0.338 gm/cc 0.378 gm/cc 0.406 gm/cc 0.435 gm/cc Angle of Repose 48 46 47 49 Compressibility index 23% 29% 31% 33% Hausner ratio 1.3 1.4 1.45 1.5

• A blend uniformity study using the RLD formulation. It is found that de-mixing occurs

during a long time (60 minutes) mixing process and RSD lower than 6% were never obtained.

• A direct compression of the blend was attempted. The blend uniformity RSD was higher than 6% and when compressed the drug product content uniformity RSD was even higher and thus unacceptable. In the direct compression, the individual drug and diluent particles are still present, and all the components can behave as individual particles. Therefore there is a risk that acetriptan could segregate or agglomerate to lead to in-homogeneity of powders after mixing and prior to compression.

Based upon the above studies, dry granulation is selected for manufacture of this drug product. Wet granulation is excluded due to thermal degradation of API as shown in the stability tests. The use of wet granulation with an organic solvent was also excluded because of the desire to avoid the environmental considerations involved. For dry granulation formulation, the powder particles of API and diluents are aggregated under high pressure to form a ribbon and then break down to a product of granules by milling before compression. Since the properties of the individual drug and diluent particles are masked (at least to a certain extent) by the dry granulation, the quality of tablets is directly influenced by granules (mixtures of API and diluents) instead of the individual drug and diluent particles. Therefore, control of size distribution and flow property (e.g., loose and packed densities) of granules is potentially critical for final blending and compression processes.

2.1.2 Excipients Note to Reader: Excipient compatibility is an important part of understanding the role of inactive ingredients in product quality. It should be based on the mechanistic understanding of the API, its impurities, excipients and their impurities, mechanism of degradation and potential process conditions for drug product manufacture. A scientifically sound approach should be used in constructing the compatibility studies. Evaluation of binary mixtures is one of many potential empirical approaches. The commercial grades of the excipients are not provided in this example to avoid endorsement of specific products. However, in an actual pharmaceutical development report the names of the commercial grades are expected. The initial identification of potential excipients is described in section 2.2.1 (Formulation Development). Standard pharmaceutical grade excipients were used and all excipients met compendial standards. The magnesium stearate used was of vegetable origin. The lactose monohydrate used was certified to be free of melamine by the manufacturer.


22

Lactose Monohydrate: The potential impurities of lactose monohydrate are melamine and aldehydes. Based on the chemical nature of the drug substance, no interaction is expected between the drug substance and lactose and its impurities. The supplier has certified that the lactose is free of melamine in addition to TSE/BSE certification. Microcrystalline Cellulose: MCC is widely known excipient used for direct compression. The grade chosen is a directly compressible grade. Based on the chemistry of drug substance and the MCC, no potential interaction is expected between the drug substance and MCC and its impurities. Though it is reported in the literature regarding the physical binding / adsorption between the MCC and drug substance, no such physical interaction was found evident in our formulation dissolution studies. Croscarmellose Sodium: Being a super disintegrant, croscarmellose is hygroscopic in nature. It swells rapidly about 4-8 times of it original volume when it comes in contact with water. There are no known impurities in this excipient. Based on the understanding of this excipient and the drug substance, no chemical interaction is expected. Based on prior experience with roller compaction, initial selection of excipient grade and supplier was based on material that had been used in successful products produced by roller compaction.

Table 10 Excipient grade and supplier identification Excipient Supplier Grade Prior Use in Roller Compaction

Lactose Monohydrate A A03 ANDA 123, ANDA 456 Microcrystalline Cellulose B B03 ANDA 123, ANDA 456 Croscarmellose Sodium C C03 ANDA 456 Talc D D03 ANDA 789 Magnesium Stearate E E03 ANDA 123, ANDA 456

These initial grade selections were verified during pharmaceutical development.

2.1.2.1 Excipient Compatibility Studies Drug/excipient compatibility was assessed through HPLC analysis (method 41 and 125 a) of binary mixtures of drug to excipient, at a 1:1 ratio in the solid state, stored at 25°C/60% RH and 40°C/75% RH (open and closed conditions) for 1 month. An interaction was seen with magnesium stearate at 40°C/75%. The interaction causes the lower assay of acetriptan. The mechanism for this interaction was indentified as formation of a magnesium stearate-acetriptan adduct (AD1) involving the stearic acid.

Table 11 Excipient Compatibility Condition Assay Method


40°C/75% RH (1 month) % Assay Observed Degradants Lactose Monohydrate/API (1:1) 99% N/A Microcrystalline Cellulose/API (1:1) 99% N/A Croscarmellose Sodium /API (1:1) 99% N/A Talc/API (1:1) 99% N/A Magnesium Stearate / API (1:1) 95% AD1: 4%


23

To further evaluate if this potential interaction could cause drug instability an additional experiment was performed in which several different mixtures of drug and excipients were prepared. The first mixture consisted of drug and all excipients in the ratio that would be used in the finished product. In subsequent sets, one excipient was removed at a time. These mixtures were stored at 25°C/60% RH and 40°C/75% RH (open and closed conditions) for 1 month. No loss in assay was observed in any of these mixtures; neither at 40°C/75% nor at 25°C/60% RH. Therefore, magnesium stearate was still used, but contact of the drug substance with magnesium stearate was limited by only using extra-granular magnesium stearate. Subsequent assurance of compatibility was provided by long-term stability data on formulations used in the pilot PK study and the ongoing stability studies on the formulation proposed for commercialization. The impurity method is able to identify and quantify AD1. AD1 was BLQ in the long-term stability study and is constrained by the limit for any unspecified impurity.

Table 12 Excipient Compatibility Condition Assay Method


40°C/75% RH (1 month) % Assay Observed Degradants All excipients 99% N/A All excipients except Microcrystalline Cellulose 99% N/A All excipients except Croscarmellose Sodium 99% N/A All excipients except Talc 99% N/A All excipients excpet Magnesium Stearate 99% N/A

Conclusion: There is no incompatibility with the selected excipients except for the noted interaction with magnesium stearate.

2.2 Drug Product

2.2.1 Formulation Development Note to Reader: In a QbD approach to formulation development there should be an understanding of how the components of the formulation affect the ability to meet the critical quality attributes identified in the quality target product profile. This understanding can be mechanistic in nature or empirical (derived from experiments). In this example, formulation study #1 establishes how particle and disintegrate level ensure the desired rapid dissolution. In a QbD approach, risks to product quality are mitigated. In this example, there is an investigation of the identified risk of impurity generated by interaction with magnesium stearate. An QbD approach to excipient grade selection should consider the critical material attributes of the excipients. In this example, the role of excipient particle size is considered in the choice of excipient grade and monitoring of excipient particle size becomes part of the control strategy. This formulation development example illustrates the role of risk assessment. Those formulation factors that are identified as high risk (known to affect CQA) or moderate risk (potential to affect CQA) should be addressed. This may be through studies or mechanistic understanding that establish a design space or proven range (desired QbD approaches) or through specification


24

that limit variation in these variables (the approach taken here on excipient particle size). Elements identified as low risk still may require control. For example, post-approval changes to the amount of low risk excipient talc may still need to be reported to FDA as a supplement. Formulation development may vary from firm to firm. This is one possible example, but alternative approaches are possible. Formulation development took place on a 100-1000 g scale (lab). The first prototype formulation selected for development followed the qualitative composition of the reference product (see Table 2). This formulation (listed in Table 13) was used in a pilot PK to establish that the in vitro dissolution test would be useful to guide development. Literature and historical formulation information suggested that a higher ratio of MCC/lactose might provide better roller compaction and tableting. This was investigated during formulation optimization studies. Because of the potential for degradation linked to magnesium stearate, the level of this excipient was minimized and limited to extragranular use. It was not desired to introduce a new excipient that was not found in the reference product. The following considerations supported the selection of the final formulation including

• The differences between available grades of excipients. • A laboratory scale study to select the particle size, MCC/lactose ratio and disintegrant

level. • A laboratory scale study to find the minimum magnesium stearate level (this study

resulted in the use of 0.5% magnesium stearate in the final formulation). These studies were selected because our risk assessment (Table 15) indicated that these variables had the highest potential to alter the drug product CQA. The conclusion of the formulation development studies is that acceptable ranges for the high risk attributes have been established and are included in the control strategy. An MCC/lactose ratio that gave acceptable dissolution was selected for further development. Because content uniformity is a CQA that is also strongly affected by the manufacturing process, risk mitigation for the factors that influence it will be considered in process development on equipment that is closer to the proposed commercial process. Note to Reader: In this risk assessment for formulation development the detailed manufacture process was not established. Thus in this risk assessment, risks were rated assuming that for each formulation attribute that changed, an optimized manufacturing process would be established. For example, the lactose/MCC ratio is rated as a medium risk in this assessment because the tablet compression can be adjusted to make tablets from different ratios. If the compression process were established or fixed, then a change in lactose/MCC would be high risk because it would likely cause failure of compression. The results of risk assessment depend on assumptions and context.


25

In this example, the results of the risk assessment process were mapped on to low, medium and high categories. In general, OGD recommends that the high category be reserved for those risks that usually would need to be addressed by actual studies to establish acceptable ranges. The medium risk contains those situations where there is a possibility for a change in factor level to affect product quality, but also knowledge and experience that often small variations in this factor do not adversely affect pharmaceutical quality. Risk rated as low risk are for those factors generally accepted as not altering product quality when used in accordance with cGMP and the sponsors quality system. Low risk factors likely will have wide range of acceptability. As in this example, medium risk factors may be subject to further study in pharmaceutical development to establish ranges, establish formulation robustness, or to choose optimal values. In contrast, ranges for low risk factors would generally be proposed based on prior knowledge or understanding of acceptable values.

2.2.1.1 Development PK Study 1001 Note to Reader: For low solubility drugs pilot PK studies are invaluable to demonstrate that the in vitro dissolution used in QbD is appropriate. When pilot PK studies are conducted the following is an example of how they should be described in the development report and used to support controls on critical attributes such as particle size and understand the relation of in vitro dissolution and in vivo performance. Inclusion of fast, medium and slow dissolving formulations helps to determine if there is a useful in vivo in vitro relationship. A pilot PK study in 6 healthy subjects (four way crossover: three test product administration and the RLD at a dose of 20 mg) investigated the effect of particle size on in vivo bioavailability because of the low solubility and the significant effect of particle size on in vitro dissolution. The prototype formulations used a very similar formulation to the RLD (also with 10% drug load) but differed in particle size.

Table 13 Prototype Formulation Used in the Pilot PK Study Test Product

Ingredient Function Weight/tablet % (w/w) Acetriptan, USP Active 20.00 mg 10

Intragranular Excipients Lactose Monohydrate, NF Filler 82 mg 41 Microcrystalline Cellulose, NF Filler 80.0 mg 40.00 Croscarmellose Sodium, NF Disintegrant 6 mg 3 Talc, NF Glidant/Lubricant 5 mg 2.5

Extragranular Excipients Magnesium Stearate, NF Lubricant 2 mg 1 Talc, NF Glidant/Lubricant 5 mg 2.5 Total Weight 200.0 mg 100%

*Magnesium stearate level estimated by EDTA titration of magnesium. The dissolution data from these formulations and the PK results are presented in following table and figures.


26

Table 14 Pharmacokinetic Parameters (Geometric Mean) from Pilot Study Parameter d90 60 µm d90 45 µm d90 30 µm RLD

AUCinf (ng/ml hr) 7299.83 8571.16 8636.5 8723.77

AUC0−t (ng/ml hr) 5431.1 8259.39 8432.34 8532.7

Cmax (ng/ml) 198.33 232.43 246.04 241.21 Tmax (hr) 2 1.5 1.5 1.5

t1/2(hr) 24.11 24.17 24.13 24.11

AUC Ratio (Test/RLD) 0.84 0.98 0.99

Cmax Ratio (Test/RLD) 0.82 0.96 1.02

Figure 5 Mean PK profiles from the pilot study


27

Figure 6 Dissolution of acetriptan drug product as a function of particle size in 0.1N HCl and 1% SLS (left)

and 2% SLS (right) compared to the dissolution of the RLD drug product.


28

0.8

0.85

0.9

0.95

1

1.05

40 50 60 70 80 90 100

% Dissolved in 30 minutes

PK P

aram

eter

Rat

io

1% SLS AUC1% SLS Cmax2% SLS AUC 2% SLS Cmax

Figure 7 AUC and Cmax ratios as a function of percent dissolved at 30 minutes. These data indicate that particle size of 45 µm or less has a limited effect on pharmacokinetic profiles. Therefore the dissolution effects observed suggests that a 2% SLS dissolution media with a 30 minute endpoint distinguished passing from failing PK profiles while a 1% SLS media was more sensitive to formulation variables.

2.2.1.2 Excipient Grade Selection Microcrystalline cellulose and lactose monohydrate form about 80% of the total drug product composition. Microcrystalline cellulose and lactose monohydrate are among the commonly used diluents for dry granulation formulations, individually and in combination with each other, as they exhibit appropriate flow and compression properties. The particle size and particle properties have the potential to affect the content uniformity of the blend prior to roller compaction stage as well as after roller compaction and milling stages. Based on the shape and topography (surface roughness) of lactose, we have experience that similar grades of lactose from different sources did not cause any differences in the output variables (responses) during roller compaction. Based on prior experience (Table 10) we selected a particular grade of lactose and as indicated in the risk assessment table (Table 18), we expect to keep the excipient grade for lactose (particle size d50: 70-100 µm) as a fixed element. Based on our pre-formulation work and literature, we know that the MCC undergoes deformation during compaction since it is a fibrous material and ductile in nature. Not all grades


29

of MCC may be suitable for use in roller compaction. In our initial product development, a grade of microcrystalline cellulose with similar particle to the active (d50: 50-100 µm) that has also previously been used in a roller compaction process (Table 10) was selected and considered as a fixed element. During process development robustness of the manufacturing process was demonstrated by investigation of variation of the selected excipient grades. The specifications of the inactive ingredients comply with the United States Pharmacopeia/National Formulary (USP/NF), European and Japanese pharmacopoeias. Additional controls, above those in the pharmacopoeia, include particle size limits on the two major excipients [lactose (d50: 70-100 µm) and microcrystalline cellulose (d50: 50-100 µm)]. Material within these ranges was used in all further formulation studies.

2.2.1.3 Formulation Risk Assessment To identify variables for further study a risk assessment was conducted. This risk assessment included prior knowledge and experience with related formulations and information about acetriptan from published literature. Because the final manufacturing process was not established at the time of this risk assessment, changes that could be mitigated by adjustments to the manufacture process were rated as lower risk. These factors would be reconsidered during process development. In the risk assessment process, quantitative risk priority numbers were mapped onto three categories (high, medium and low).

Table 15 Initial Formulation Risk Assessment Formulation Attribute DP CQA DS

Particle Size

Talc Level

MCC/ Lactose Ratio

Lactose Grade

Lactose Particle

Size (within grade)

Disintegrant Level

MCC Grade

MCC Particle

Size (within grade)

Magnesium Stearate

Level

Assay Low Low Low Low Low Low Low Low Low Impurity Low Low Low Low Low Low Low Low High CU High Low Low Medium Medium Low High Medium Low Dissolution High Low Medium Low Low High High Low High

Drug substance particle size was considered high risk for dissolution based on the data in Figure 4. Disintegrant level was high risk for dissolution because of the need for rapid dissolution and the need for product disintegration not to be a limiting step. Drug substance particle size was considered a high risk for content uniformity based on prior knowledge about the properties of other micronized drug substances. The MCC/lactose ratio was considered medium because it was known to affect dissolution via the hardness of the tablets, but the hardness would usually be adjusted in the compression step of the process. Change in excipient grade was considered to have a potential impact on product quality. Since the ability of different grades of MCC to be compressed after roller compaction was not known, the risk was considered high. Particle size of excipients within grade was considered as a medium risk of affecting content uniformity because different grades of excipients with different particle size from the active could change the blend uniformity unless the manufacturing process (blending) was adjusted to compensate.


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2.2.1.4 Formulation Study #1 Formulation Optimization The formulation component level definition study was designed to select the MCC/lactose ratio and disintegrant levels and ensure that there was no interaction of these variables with drug substance particle size. This study also established the robustness of the proposed formulation. A mixed level design was used with 9 trial runs to study the impact of three formulation factors on the three key response variables. The factors studied were:

• MCC/Lactose Ratio: 1 to 3 • Disintegrant (Croscarmellose Na) Level: 1% - 4% (intragranular) • Acetriptan Particle size d90: 15, 30 & 45 µm

Magnesium stearate level was set at 1% and the total tablet weight was fixed at 200 mg. The response variables studied were:

• Tablet hardness at a fixed compression pressure • Dissolution average at a fixed tablet hardness target of 12 kP (a range of 10-14 kP was allowed) • Tablet content uniformity

Tablets were compressed at three compression pressures and samples were also collected at a target hardness of 12 kP; the compression pressure was adjusted to achieve this hardness. A constant tablet weight of 200 mg was used with the filler amount adjusted to achieve the target weight. Figure 8 presents the interaction profile for the hardness response at a fixed compression pressure. Only the MCC/lactose ratio (R) has any effect on hardness at a fixed compression force.


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Figure 8 Interaction profile for Hardness Response at Fixed Compression Pressure In order to understand the impact of the formulation variables on dissolution, the relationship was examined at a fixed tablet hardness target of 12 kP. The hardness was fixed at 12 kP because a high hardness would be expected to be the worst case for the dissolution response. If dissolution were studied at a fixed compression pressure, the results could be confounded by the impact of the other variables on the tablet hardness. In Figure 8, as the ratio increases the tablet hardness increases at a fixed compression pressure. This increase in hardness would confound any potential impact the other variables have on dissolution because the associated increase in hardness usually results in a decrease in dissolution. Figure 9 presents the results for dissolution at a set target tablet hardness of 12 kP. This interaction profile also shows that there is no effect of disintegrant level between 3-4%. The dissolution response falls below 80% when the lowest disintegrant levels are combined with the largest particle size. A contour plot for the 30 minute dissolution response at fixed tablet hardness is presented in Figure 10. In the upper left region there is a combination of disintegrant and particle size that leads to slower than desired dissolution. Because of this observed trend to failure both the particle size and disintegrant levels are considered to be critical. There were no trends identified for content uniformity %RSD response. The measured tablet uniformity % RSD responses are 2.6% or lower, which meets the attribute target criteria of < 5.0%. The effect of process variables on blend uniformity and content uniformity will be investigated during process development on a larger scale process. The conclusions from the formulation component level definition study provided the basis for formulation component level selection. An acceptable predicted response was demonstrated for content uniformity % RSD over the ranges studied. The dissolution response at a fixed tablet hardness of 12 kP shows that at low levels of disintegrant the largest particle size studied may not meet dissolution expectations.


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70

75

80

85

90

95

100

DIS

S (%

dis

solu

tion

at 3

0 m

in)

15 30 45PS (particle size (D90))

70

75

80

85

90

95

100

DIS

S (%

dis

solu

tion

at 3

0 m

in)

1 2.5 4DISINT (disintegrant) Figure 9 Interaction Profile for Dissolution Response at a Set Target Tablet Hardness of 12kP.


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Figure 10 Dissolution Response for 10% Drug Load at a Target Tablet Hardness of 12kP

2.2.1.5 Formulation Study #2 Magnesium Stearate Magnesium stearate was linked adduct formation with API. The goal of this study is to find the minimum level of magnesium stearate needed for tableting. Most runs in formulation study #1 used 1% magnesium stearate. A portion of pre-lubrication blend from formulation study #1 was not tableted and reserved. This material was used in formulation study #2. Two talc levels were used to evaluate if increase talc could compensate for a reduction in magnesium stearate. The factors studied were as follows:

• Magnesium Stearate Level: 1%, 0.5% & 0.1% (extragranular) • Talc Level: (I) 2.5%,(intragranular) and 3.5% (extragranular); (II) 2.5% (intragranular) and 2.5% (extragranular)

The response variables studied were the same as used in formulation study #1: • Tablet hardness at a fixed compression pressure • Dissolution average at 30 minutes at a set target hardness of 12kP • Tablet content uniformity

The conclusion of this investigation was that the 1% and 0.5% magnesium stearate levels replicated the previous results while the 0.1% level demonstrated significant compression related issues such as tablet picking and sticking indicating a problem with consistent tableting. An


34

increase in the amount of talc did not resolve the problem. Based on this result, 0.5% magnesium stearate was used in the final formulation rather than the 1% that was used in formulation study #1.

Table 16 Results from Formulation study#2 Magnesium Stearate Level

Talc Level Tablet hardness at fixed compression

30 min Diss at hardness of 12kP

Tablet content uniformity (% RSD)

1% I 10 89 2.0 0.5% I 9.9 92 2.4 0.1% I Fail to tablet Fail to tablet Fail to tablet 1% II 9.8 88 1.9 0.5% II 9.7 93 2.2 0.1% II Fail to tablet Fail to tablet Fail to tablet

2.2.2 Conclusions of Formulation Development The conclusion of formulation development was the selection of a formulation to move into process development. The effects of drug substance and excipient particle size on the manufacturability would be investigated further in larger scale process studies.

Table 17 Formulation Selected for Process Development Test Product Reference Product

Ingredient Function Weight/tablet % (w/w) Weight/tablet Acetriptan, USP Active 20.00 mg 10 20.00 mg

Intragranular Excipients Lactose Monohydrate, NF Filler 43 mg 21.5 Present Microcrystalline Cellulose, NF Filler 120.0 mg 60.00 Present Croscarmellose Sodium, NF Disintegrant 6 mg 3 Present Talc, NF Glidant/Lubricant 5 mg 2.5 Present

Extragranular Excipients Magnesium Stearate, NF Lubricant 1 mg 0.5 2 mg* Talc, NF Glidant/Lubricant 5 mg 2.5 Present Total Weight 200.0 mg 100% 200.0 mg

*Magnesium stearate level estimated by EDTA titration of magnesium. These formulation development studies addressed the identified risks:


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Table 18 Results of Formulation Development on Identified Risks Formulation Attribute DP CQA DS

Particle Size

Talc Level

MCC/ Lactose Ratio

Lactose Grade

Lactose Particle

Size (within grade)

Disinte- grant Level

MCC Grade

MCC Particle Size

(within grade)

Magnesium Stearate

Level

Assay Low Low Low Low Low Low Low Low Low Impurity Low Low Low Low Low Low Low Low Not

Critical Addressed by Design

CU Not Critical on lab scale

Confirm on

larger scale

Low Low Fixed Criticality Undetermi

ned Addressed

by Constraint on Grade

Low Fixed Criticality Undetermine

d Addressed

by Constraint on Grade

Low

Dissolution

Critical PAR

Identified

Low Not Critical

PAR Identifi

ed

Low Low Not Critical PAR

Identified

Fixed Low Not Critical PAR

Identified

Note: PAR: Proven Acceptable Range

2.3 Process Development Note to Reader: There are various approaches to process development used in the ANDA industry. This is one of many possible examples. All QbD approaches to process development should identify the critical process parameters for the unit operations. A firm may choose to do this through reference to documented prior knowledge or through empirical experiments on a range of process scales building toward the exhibit batch and proposed commercial scale process. This example provides study ProcDev-1 as an example of experimentally determining critical process parameters when there is variation in the characteristics of input materials. Not all products may be studied this extensively unless there was a problem observed on attempts to scale up. QbD emphasizes building understanding prior to failures on scale up. The multivariate experiment described here would be a step toward defining a design space on these variables. If a design space was not the goal, a less comprehensive investigation may be used to define acceptable ranges. Study ProcDev-1 also illustrates how a PAT method could be validated in development and then used in scale up to ensure consistent blending. Industry will provide an alternative to study ProcDev-1 based on prior knowledge about similar formulations.


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In a QbD approach, the pharmaceutical development should explain how knowledge is transferred across process scale. In this example, we limit this discussion to the blending unit operation. Introduction Based on the physico-chemical properties of the API, roller compaction was selected as an appropriate manufacturing process. The API is sensitive to heat, which would preclude wet granulation, due to chemical instability during a drying process. The use of wet granulation with an organic solvent was not considered because of the desired to avoid the environmental considerations involved. In addition, the API physical properties (mixibility) precluded direct compression at the concentrations required. Tablet coating was also precluded due to chemical instability during drying. A laboratory scale process (500 g, 2,500 units) was implemented for use in formulation evaluation. From prior experience we have found that successful laboratory scale mixing and uniformity needs to be verified on pilot scale equipment that is designed to be more predictive of the exhibit batch equipment. The laboratory scale process was used for the development PK study 1001. Once the formulation was finalized, a pilot scale process (1.5 kg 7,500 units) was developed to begin to identify critical process parameters. The pilot scale used equipment that was a scale-down of the expected bio-batch and commercial process equipment.

Table 19 Process scale summary Scale Mass Units Lab (Formulation Development) 500 g 2,500 units Pilot (Process Development) 1.5 kg 7,500 units BioBatch 30 kg 150,000 units Commercial (Proposed) 90 kg 450,000 units

A risk analysis, in accordance with ICH Q9, was used to establish which variables and unit operations were likely to have the greatest impact on product quality. This initial risk assessment is shown below.

Table 20 Initial Risk Assessment for Process Development

** Pharmacy refers to the accuracy of the DS and excipient weights

Variable and Unit Operations DP CQA Pharmacy** Blending Roller

Compaction Milling Final

Lubrication Compression

Assay High Low Low Low Low High

Impurities Low Low Low Low Low Low

Content Uniformity

Low High High High Low High

Dissolution Low Low High High High High


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This pilot scale process was used in studies to address the high risk elements by identification and control of critical process parameters

• A DOE to optimize the blending process parameters • A DOE to optimize the roller compaction process parameters • An investigation of lubrication time • An investigation of tableting parameters • An investigation of the impact of in-process material parameters on tablet compression

Table 49 indicates how these results were used in a control strategy that mitigates the risks.

2.3.1 Identification of Critical Process Parameters Process parameters and material attributes are identified as critical when a realistic change can result in failure to meet the QTPP. Process parameters are not critical when there is no trend to failure and there is no evidence of significant interactions within the proven acceptable range (PAR).

2.3.1.1 Pre-Granulation Blending

2.3.1.1.1 Identification of Blending Process Parameters and Initial Risk Assessment Based on our risk analysis, blending was identified to be a potential risk to both blend and tablet content uniformity. However, by placing appropriate controls on both the materials and the process parameters, the risk can be adequately reduced to an acceptable level. The following figure describes the cause and effect diagram of the blend uniformity.


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DS MCC LM CCS

DS MCC LM CCS

Sampling

Analysis PAT

Temperature

RH

Operator

Order of Addition

Blender Type RPM

# of Revolutions

Blend LOD Material Attribute: PSD Sampling & Analytical Technique Manufacturing Conditions Process Parameters

Figure 11 Fishbone Diagram for Blending Process. 2

Table 21 Blending Process Parameters Input Initial Risk Assessment Initial Strategy

Material Attributes Raw Material LOD Not Critical Raw Material COA Drug Substance Particle Size Potentially Critical PAR: d90 < 45 μm from Diss

Investigate Blending Lactose Particle Size Potentially Critical Fixed: d50 70-100 μm MCC Particle Size Potentially Critical Fixed: d50 50-100 μm CCS Particle Size Not Critical Compendial Standard

Process Parameters Blender Type Potentially Critical Fixed: V-blender Order of Addition Potentially Critical Fixed: see Batch Record RPM Potentially Critical Fixed: 16 rpm Number of Revolutions Potentially Critical Investigate Load Level Potentially Critical Fixed: 67% Environment Temperature Potentially Critical Fixed: 70ºF ±5%. Environment RH Potentially Critical Fixed: 40%-70%

2 Abbreviations used include: LOD Loss on drying; CCS Croscarmellose Sodium; LM Lactose Monohydrate; MCC Microcrystalline Cellulose; DS Drug Substance; RH Relative Humidity; RPM Rotation per minute; PAT Process Analytical Technology

Blend Uniformity


39

Risk Assessment of Factors (Input Variables): The factors potentially affecting BU were analyzed for risk assessment based on our previous experience.

Material Attribute LOD: The LOD of the materials was not considered critical.

Material Attribute PSD: The effect of drug substance and excipient particle size on blend uniformity was not definitively established in the lab scale studies. The level of croscarmellose sodium is low and in our past experience we did not observe this kind of super disintegrant playing a role in mixing. Therefore we have chosen to challenge the process and the PAT method with different grades of MCC and lactose as well as using the three different drug substance size distributions available d90.

Sampling & Analytical Technique: The sampling procedure is critical since the drug substance is cohesive and static. The operators have been trained to sample the blend in such an environment. Therefore, the sampling technique is adequately established as a routine procedure and not considered as a variable. PAT Method: Study is needed to establish the PAT method therefore it is considered a high risk factor.

Manufacturing Conditions: The temperature in the manufacturing area is controlled at 70 ºF with a variation of ±5%. The ambient air is conditioned to carry a humidity of not more than 70% and not less than 40%. Thus, both the temperature and relative humidity were adequately controlled.

Process Parameters: The order of addition is established in the unit operation. The v-blender is the most common equipment used in the company. Therefore, these input variables will not be changed. The load level will also be fixed and preserved on scale up. The RPM was fixed based on a scale down of the intended mixing speed in the proposed commercial process The effect of number of revolutions was evaluated. Note that mixing time is determined by RPM and number of revolutions.

2.3.1.1.2 Study ProcDev-1: A DOE study of Blending Process Parameters

Objective and Introduction The manufacturing process involves a blending step followed by roller compaction to obtain uniform granules for compressing into tablets. Though the purpose of roller compaction is to produce uniform granules with a narrow distribution and to improve the blend uniformity of the final blend before compression, a DOE was performed to study the effect and interaction of CMA and CPP on pre-roller compaction mixing. The final blend includes approximately 10% API and 90% diluent, which is mostly lactose monohydrate and MCC. Our developmental studies have indicated that a drug substance and excipient blend without adequate blend uniformity prior to roller compaction might produce drug product with higher acceptance value of CU and thus poses high risk for rejecting a batch. Therefore, the purpose of the study were


40

• to evaluate the effect of combination and interaction of both CPP and CMA on blend uniformity and to mitigate the risk associated with the final blend uniformity before compression process

• to decide the adequacy of the blend uniformity in pre-roller compaction mixing based on the final blend uniformity (BU) before compression

• To establish a PAT method for blending endpoint identification.

Method for Determining Blend Homogeneity The BU was determined by collecting the blend samples as a function of mixing time and analyzing the samples with a validated HPLC method. The chromatographic conditions were same as the assay method except the sample preparation. In this study, data from sampling was used to cross-validate the uniformity data obtained from an NIR method. The reported BU data come from the fixed time sampling.

Batch Size for Studies: The batch size was kept at 7,500 unit tablets (corresponding to 194 mg per tablet pre-RC (talc and magnesium stearate are added after RC), equivalent to 1.455 kg.

Process Equipment: The bulk density of the blend was found to be 0.43 gm/cc. Based on the total volume of 3.33 L, a 5 L twin-shell blender with an intensifier bar was chosen. This entire study was carried out in our pilot plant and the high shear twin shell blender was fully validated and qualified. Similarly the sampling thief was calibrated to draw predetermined amount of sample for the analysis. Sampling Protocol: The BU ensures the uniformity of the of the drug substance distribution before the roller compaction. Since the DS has the tendency of being cohesive and electrostatic in nature, geometric mixing was performed. In addition, due to the nature of this drug substance, the thief was electrically grounded to avoid the static that may disturb the powder bed. The blend was transferred into a stainless steel drum before sampling. The sampling was performed at 3, 6, 9 and 12 o’clock positions and middle position at one level yielding 10 samples. The sample volume represented 2.4 to 3.6 times of blend equivalent to 455 mg to 682 mg of blend. The thief sample volume was calibrated to take the blend within that range. The samples were analyzed without any further transfer / treatment and the BU of all ten samples were reported as mean ± RSD. The samples were taken every five minutes for 60 minutes based on our trial experiments. The modified HPLC method that tests the sample is validated for assay, which is used for testing the BU samples too. NIR Method: Both traditional sampling and measurements of uniformity by a NIR sensor were conducted and compared and used for cross-validation of the NIR method. The NIR sensor makes one measurement per revolution. The NIR spectrum of the active and excipients allow sufficient specificity for the active ingredient. A validation report of the NIR method including its chemometric model and cross-validation with uniformity measured by sampling is included in the application


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Parameter Ranges The factors and their ranges are given below:

Table 22 Factors and Range

Levels Used Factors -1 0 +1

Response

MCC (d50) NA 75 µm 125 µm Lactose (d50) NA 80 µm 130 µm DS (d90) 15 µm 30 µm 45 µm

Blend CU

MCC: This excipient is available in different grades. Based on the given supplier and the method of manufacturing, the shape and the aspect ratio of the MCC may differ. However, within a given supplier, the shape and aspect ratio remain the same. Thus, we have selected two different grades of MCC from same supplier one with a smaller and one with a larger particle size. The primary difference in these grades was the particle size distribution, which was adequately described by d50 since the particle size distribution exhibited a consistent distribution. Level 0 is the grade used in formulation development and the pilot PK study with vendor particle size limit of d50: 50-100 µm. Level 1 is the closest grade from the same vendor with a particle size limit of d50: 100-150 µm. Lactose: Two grades with larger and smaller size particles were evaluated to ensure formulation robustness. Level 0 is the grade used in formulation development and the pilot PK study with vendor particle size limit of d50: 70-100 µm. Level 2 is the closest grade from the same vendor with a particle size limit of d50: 120-150 µm. Drug Substance: The particle size distribution of the drug substance was based on the in-vitro performance of the drug product, namely the dissolution profile. Based on early experiments, the dissolution rate of the drug product manufactured with the drug substance d90 ranging from 15 to 30 µm did not display any significant difference; also 30 and 45 µm were bioequivalent to the RLD in the pilot study. Thus, the drug substance particle size distribution was evaluated solely for the manufacturing process robustness. As described in Table 8 the single value, d90 was taken as the indicator of the particle size distribution of the drug substance. Mixing Speed: The mixing speed was held constant in these experiments. Our exhibit and commercial scale equipment use a fixed mixing speed. The pilot scale experiments use a different mixing speed that corresponds to a similar tip speed in the commercial scale equipment. The agitator bar speed was kept constant in all the experiments.

Response: The measured effect was the Relative Standard Deviation of the Blend Uniformity of 10 samples taken as a function of time. Though the mixing was continued for a period of 60 minutes, all the RSD of the samples reached a plateau after 30 minutes. Thus, the BU RSD of the samples of each run was taken at 40th minute. Thus, the experiments runs and the composition


42

based on the factors are given below. The CU RSD was determined from tablets produced from these blends.

Table 23 Experiment Runs, Factors and Responses Run # A (MCC) B (DS) C(Lactose) Response (BU RSD)

(Before Roller Compaction) Response (CU RSD)

1 0 (75) -1 (15) +1(130) 6.5 2.5 2 +1(125) -1 (15) 0(80) 8.6 5.6 3 0 (75) +1 (45) 0(80) 4.9 1.9 4 +1 (125) +1 (45) +1(130) 6.0 2.0 5 0 (75) 0 (30) 0(80) 4.8 1.8

The NIR instrument provided continuous measures for uniformity that were consistent with the data obtained from sampling.

0

5

10

15

20

25

30

35

40

0 5 10 15 20 25 30 35 40

Time (min)

NIR

Var

iatio

n (%

CV)

Run 1

Run 2

Run 3 Run 4

Run 5

Figure 12 Uniformity determined by NIR measurement

A commercially available statistical software was used for following purposes: selecting DoE, establishing the model, creating the random sequence for the experimental run, further input of experimental run results (BU RSD), analyzing the data, obtaining diagnostics statistics report, plotting response surfaces (contour plots) and three dimensional plots.

The data suggests the BU RSD was lowest when the drug substance particle size was at the 30 µm level and the when the MCC level was maintained at its standard level. However, based on our further studies (ProcDev-2-4) on roller compaction, final blending, compression, adequate content uniformity of the final drug product was achieved (target RSD of less than 4%) as long as the RSD of the pre-roller compaction BU was less than 6.5%. In addition, model based


43

interpolation of the data suggests the BU would be acceptable when the drug substance d90 was above approximately 25 µm. Lactose grade did not appear to have a significant affect. This confirmed and justified the use of the selected grade.

As described earlier, the blends from all runs were granulated by roller compaction, milled, lubricated and compressed. The final drug product content uniformity was studied and correlations were made. Based on these studies, the RSD of the final content uniformity (CU RSD) was less than 2.5% as long as the RSD of pre-roller compaction BU was less than 6.5%. In addition, none of these runs generated a final drug product content uniformity more than 6%. In further experiments, BU will be determined by the NIR method.

2.3.1.1.3 Critical Process Parameters for Pre-Granulation Blending Pre – roller compaction blending was studied empirically and the interactions between variables were analyzed by mechanistic means. To begin with, the key factors involved in this mixing operation were subjected for risk assessment. All the possible factors were identified, analyzed and evaluated. Most of the factors were either non-critical or controlled from the source. Justification of limits was sought for MCC and drug substance particle size and also for mixing time too. Based on the statistical modeling, a flexible and robust manufacturing operation was designed to be insensitive to the fluctuation in the particle size distribution of MCC and drug substance.

Table 24 Blending Unit Operation: Determination of Critical Parameters Input Criticality Conclusion Control Strategy

Material Attributes Raw Material LOD Assumed Not Critical Raw Material COA Drug Substance Particle Size (d90) Critical PAR: < 45 μm (Dissolution)

PAR: 25-45 μm (Blending) Lactose Particle Size (d50) Not Critical PAR: 80-130 μm MCC Particle Size (d50) Critical Fixed: 50-100 μm CCS Particle Size Assumed Not Critical Compendial Standard

Process Parameters Blender Type Criticality Undetermined Fixed: V-blender Order of Addition Criticality Undetermined Fixed: see Batch Record RPM Criticality Undetermined Fixed: 16 RPM Number of Revolutions Not Critical Blend to BU endpoint Load Level Criticality Undetermined Fixed: 67% Environment Temperature Criticality Undetermined Fixed: 70ºF ±5%. Environment RH Criticality Undetermined Fixed: 40%-70%

2.3.1.2 Roller Compaction and Milling

2.3.1.2.1 Identification of Roller Compaction Process Parameters and Initial Risk Assessment


44

The initial quality risk assessment identified changes to the input raw materials (changes in API particle size, change to magnesium stearate level and change to CCS level) and process parameters for both the roller compaction and milling steps as the highest risk to product quality. Consequently an experimental approach was defined that allowed these risks to be investigated further, to determine if any controls would need to be applied.

Table 25 Risk Assessments for Roller Compaction and Milling Input Initial Risk Assessment Initial Strategy

Material Attributes Drug Substance Particle Size Not Critical PAR: 25μm - 35 μm Lactose Particle Size Not Critical Fixed See Blending MCC Particle Size Not Critical Fixed See Blending Blend Uniformity after Mixing Critical PAR: BU < 6.5% RSD

Process Parameters Roll Pressure Potentially Critical Investigate Roll Speed Potentially Critical Investigate Roll Gap Potentially Critical Investigate Feed Screw Rate Not Critical Set as Needed Roller Type Potentially Critical Fixed: AXP500 Mill Type Not Critical Fixed: Fitz Mill Mill Speed Potentially Critical Investigate Blade Configuration Not Critical Fixed: Forward Mill Screen Size Potentially Critical Investigate

Based on our experience with similar processes, particle size of components is assumed not to affect the outcome of this process step except through their effect on the input blend uniformity. Roll pressure, roll speed and roll gap are not completely independent variables because of mechanical limitations on the speeds of the feed screws.

2.3.1.2.2 Study ProcDev-2: Roller Compaction This study focused on evaluating the criticality of the process parameters for the selected formulation and drug substance and excipient material attributes.

Table 26 Factors to be Evaluated Factors investigated Range Roll Pressure 50-150 bar Roll Speed 15–22 rpm Roll Gap 2.0-3.5 mm Mill Speed 600 -1200 rpm Mill screen size 1.0 - 2.0 mm

Based on prior experience using this same equipment for related formulations, we observed that roll force was critical in all cases. Roll speed and roll gap also are usually less critical variables, but we wanted to establish more flexibility for these variables in order to allow us to adjust process flow rates on scale up to commercial production. The purpose of this investigation was to evaluate the roller compaction process parameters for the selected acetriptan particle size and magnesium stearate level. Based on our experience on


45

this unit operation, several parameters were kept within certain ranges. The horizontal feed screw speed, the vertical feed screw speed, the roll speed, and the mill speed were maintained within established ranges. The roll pressure was studied in the preliminary experiments to ensure the by-pass mass was less than 1% and the by-pass potency corresponds to the assay value of the blend fed into the roller compaction. The roll pressure was thus maintained between 50 to 150 bar. Product temperature was monitored by a non-invasive measuring device and no significant increase (> 5C) was observed. Preliminary experiments are described in laboratory data records at the site and the selected operating ranges are in the batch records for this experiments. Plan of work: All experiments are on pilot scale with the final formulation. A fractional factorial design was selected because significant interaction involving roll speed and roll gap were not expected. The replicated center point for the roller compaction DOE was used to evaluate the screen size and mill speed.

Table 27 DOE Inputs

Run Roll Speed

Roll Gap

Roll Pressure

Screen Size

Mill Speed

1 17 2.5 100 1.0 600/1200 2 17 2.5 100 1.5 600/1200 3 17 2.5 100 2.0 600/1200 4 20 3 50 1.5 600 5 13 3 150 1.5 600 6 13 2 50 1.5 600 7 20 2 150 1.5 600

Responses Based on previous experience with similar formulations, the following responses (which include both intermediate and final product attributes) were measured to assess the impact of varying input materials and process parameters during the roller compaction and milling steps. The in-process material produced by this experiment was tableted in Study ProcDev-4 under different compression forces and tableting parameters. The reported product attributes were obtained from the optimal compressions determined in Study ProcDev-4.

Table 28 Attributes Evaluated In-process Product Attributes Final Product Attributes Ribbon density Granule size distribution (GSD) d50 Granule uniformity of content Bypass mass and potency Assay of granule sieve fractions

Tablet weight Tablet hardness Tablet friability Tablet disintegration time Tablet dissolution (in 30 minutes) Tablet uniformity of content


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Table 29 Output results

Run (Mill Speed)

Ribbon Density

GSD(d50)

Granule Uniformity(% RSD)

Dissolution (% at 30 min)

1 (600) 0.77 250 2 89 2 (600) 0.76 370 3 91 3 (600) 0.75 500 4 90 1 (1200) 0.77 240 2 88 2 (1200) 0.76 360 3 92 3 (1200) 0.75 480 4 91 4 (600) 0.65 372 4 95 5 (600) 0.86 375 3 85 6 (600) 0.67 376 5 95 7 (600) 0.85 380 3 84

The only significant factor affecting ribbon density was roller pressure. The relationship between roller pressure and ribbon density is studied and data generated is given in Figure 13. The result shows that mill screen size had, by far, the most significant impact on granule size. The relative effects of mill screen size and mill speed on granule size are more clearly illustrated by the data obtained. This further highlights the dominating effect of screen size. It was also demonstrated that varying the formulation and process factors had no impact on granule uniformity of content. Furthermore, assay of the granule sieve fractions showed that the API is distributed evenly from the fine to coarse fraction further reducing the risk of downstream product segregation leading to unacceptable tablet content uniformity. There was an effect of roll pressure on dissolution. Based on this linear relationship and the observed relationship between roller pressure and tablet dissolution rate it can be concluded that a relationship between ribbon density and tablet dissolution rate also exists. The establishment of this relationship is significant, as it enables an intermediate material attribute (ribbon density) to be used as a control to assure dissolution performance.


47

Figure 13 Linear relationship is observed between Roll Pressure and Ribbon Density

2.3.1.2.3 Critical Process Parameters for Roller Compaction and Milling

Table 30 Roller Compaction and Milling Criticality Conclusions Input Criticality Conclusion Control Strategy

Material Attributes Drug Substance Particle Size Assumed Not Critical Fixed See Blending Lactose Particle Size Assumed Not Critical Fixed See Blending MCC Particle Size Assumed Not Critical Fixed See Blending Blend Uniformity after Mixing Critical PAR: BU <6.5% RSD

Process Parameters Roll Pressure Critical PAR: 75–150 bar Roll Speed Proved Not Critical PAR: 15–22 rpm Roll Gap Proved Not Critical PAR: 2.0-3.5 mm Feed Screw Rate Not Critical Determined by Roll Speed Roller Type Criticality Undetermined Fixed: AXP500 Mill Type Criticality Undetermined Fixed: Fitz Mill Mill Speed Determined Not Critical Fixed: 600 RPM Blade Configuration Criticality Undetermined Fixed: Forward Mill Screen Size Critical PAR: 1.0-2.0 mm

The conclusions from this work were:

• All dissolution values were in the target range 80-100% at 30 minutes. Roll pressure does affect dissolution

• Ribbon density was directly affected by roller pressure. This is a linear relationship and is independent of the other factors that were investigated. A relationship between ribbon density and tablet dissolution rate was also concluded


48

• All ribbon densities were in the range 0.65 – 0.86 gm/cc. • The milling studies showed acceptable process performance and generated granule d50

between 240-500 µm. • Granule Size Distribution (GSD) was only affected by mill screen size and mill speed.

Screen size was shown to be the dominating factor with mill speed imparting a minor effect. However, there was no impact of the milling parameters (and consequently GSD) on final product attributes within the ranges studied.

• Varying the input factors had no impact on granule uniformity of content. • Assay of the granule sieve fractions showed that the acetriptan is uniformly distributed • Roll speed and roll gap were determined not to be critical process parameters.

2.3.1.3 Granule Lubrication Three experiments using a 1.5 kg batch size were run, as follows: blend time 2 minutes, 3 minutes and 5 minutes. The granules obtained after the milling step were blended for 15 minutes at 12 rpm and then final lubrication blending was conducted at 2, 3, and 5 minutes. A lubrication study was performed on 1.5 kg each for 2 minutes, 3 minutes and 5 minutes to determine if lubricant blending time significantly impacted the physical properties of the resulting tablets. Because of limitation of batch size (1.5 kg) we decided to conduct the separate experiments instead of withdrawing the sample after 2 minutes, 3 minutes and stopping after 5 minutes. After each blending experiment granules were collected, content uniformity evaluated, and tablets were compressed using predetermined compression force. Time between two batches was about 1 hr. Compressed tablets were checked for appearance, hardness and dissolution (% dissolved). The % RSD for all three batches was <3.0%.

Table 31 Granule Uniformity after Lubrication Lube Time,

min BUA, % RSD:

NMT 5.0% 2 2.5 3 2.3 5 2.5

Table 32 Impact of Final Blend Lubrication Time on Physical Properties of Tablets Lube Time,

min Compression

Force, kN Hardness

4.4 – 9.5 kp Dissolution % 80% in 30 min

CU (AV)

2 6.8 -13.5 7.0 98 (95-101) 4 3 6.8 – 13.5 6.8 101 (97-102) 6 5 6.8 – 13.5 7.2 100 (97-101) 5

Material transfer operations between process steps, such as charging the final lubricated blend into the tablet press hopper, have the potential to impact the blend content uniformity when drug and excipients are not evenly distributed within each granule as a function of particle size. Precautions were taken to minimize the handling of granules. After each lubrication experiment, granules were collected in a same size container and carefully placed in the tablet press hopper


49

and tablets were compressed. During commercial manufacturing this manual transfer will be avoided by hoisting the blender above the hopper and discharging the final blend directly in the hopper from blender.

2.3.1.4 Tablet Compression

2.3.1.4 .1 Identification of Tablet Compression Process Parameters and Initial Risk Assessment Based upon the desired quality attributes of the drug product, the inputs and process variables for compression were stipulated. The product quality attributes that would be affected by the compression step include appearance, tablet weight, weight variation, content uniformity, hardness, thickness, friability, disintegration time, and dissolution rate.

Table 33 Process Parameters for Tablet Compression Input Initial Risk Assessment Initial Strategy

Material Attributes Drug Substance Particle Size Not Critical See Blending Lactose Particle Size Not Critical See Blending MCC Particle Size Not Critical See Blending Ribbon density Potentially Critical Investigate Granule size distribution Potentially Critical Investigate Granule uniformity Potentially Critical Investigate

Process Parameters Press Geometry Not Critical Fixed Tooling Geometry Not Critical Fixed Feeder Speed Potentially Critical Investigate Feeder Fill Depth Potentially Critical Investigate Pre-Compression Force Potentially Critical Investigate Compression Force Potentially Critical Investigate Ejection Force Not Critical Monitor Press Speed Potentially Critical Investigate Height of Finished Tablets Drop Not Critical Fixed

To establish the process variables that would be most significant for the critical quality attributes of the drug product, a risk assessment was performed using a Failure Mode Effect Analysis (FMEA). Press geometry, tooling geometry, ejection force and height of finished tablets drop are parameters that are routinely defined and controlled were not found to be significant risk factors. The noteworthy results of the FMEA are presented in Table 34:


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Table 34 Compression Analysis Risk Factor Effects Recommendations Pre-Compression/ Compression Force too high

Tablets too hard, disintegration time high, dissolution rate too slow.

Optimize pre-compression and compression forces.

Pre-Compression/ Compression Force too low

Tablets too soft, high friability, poor appearance.

Optimize pre-compression and compression forces.

Feeder Speed too high Tablet weights vary too much. Optimize feeder speed for consistent die fill.

Press Speed too high Tablet weights vary too much; hardness unsatisfactory, resulting into unsatisfactory dissolution rate; capping of tablets; poor appearance.

Optimize press speed.

2.3.1.4 .2 Study ProcDev-3: Tablet Compression A screening DoE was performed for assessing the impact of feeder speed and feeder fill depth on the tablet quality attributes. A result of the DoE was that changes in feeder speed and feeder fill depth over the ranges investigated had no impact on the quality of the tablets. A second DoE was performed to investigate the remaining compression parameters and to identify the target ranges. Following items were kept constant in order to evaluate just the effects of pre-compression and compression forces (Table 35):

Table 35 Input Parameters Input Material One batch of the blend (Batch #ACE200901, Pilot Scale, 1.5 kg) with

Acetriptan Particle Size: d90 = 30 μm; Magnesium Stearate: 0.5%; Ribbon Density: 0.75 g/mL (middle of the range); Tablet Target Weight: 200 mg.

pre-compression force (kN)

Compression Force (kN)

Press Speed (tblts/min) Compression Process Parameters

0.5-3.0 7.0-12.5 3000 The results of the second DoE are presented in Table 36 and Table 37.

Table 36 Results Variable Impact on the Tablets Friability Not affected with in the ranges of the pre-compression and compression forces (0.5-3.0

kN, and 7.0-12.5 kN, respectively). Hardness Directly proportional to pre-compression and compression forces. Dissolution See the tables and charts below.

Variations of disintegration time and dissolution with compression force and hardness are shown in Table 37.


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Table 37 Results Compression Force (kN)

Mean Hardness (kP)

Disintegration Time (min)

% Dissolved in 15 Minutes

% Dissolved in 30 Minutes

7.0 4.4 4.8 85.0 98.5 8.0 5.6 5.9 83.2 95.4 9.0 7.2 6.9 78.3 92.4 10.0 9.5 7.7 73.3 88.5 11.0 12.2 9.6 64.2 80.0 12.0 15.9 11.5 44.0 68.0

These results are shown graphically in Figure 14.

Compression Force vs Dissolution

0

20

40

60

80

100

120

0 5 10 15

Compression Force (kN)

% D

isso

lved % Dissolved in

15 min% Dissolved in30 min

Hardness vs Dissolution

0

20

40

60

80

100

120

0 10 20

Hardness (kP)

% D

isso

lved % Dissolved in

15 min% Dissolved in30 min

Figure 14 Dissolution Results Based upon the requirement of 80% (Q) dissolved in 30 minutes, and upon the results of the second DoE, the compression force was specified at 7.0-12.5 kN, corresponding to the hardness range of 4.4-9.5 kP. The pre-compression force, which is generally overridden by the compression force, was specified at 0.5-3.0 kN. A third experiment investigated the impact of press speed on the tablet quality. This experiment used the material in Table 35, and the pre-compression force was kept at 2.5 kN, and compression force at 9.0 kN. The only variable recorded was tablet weight variation versus press speed. For each speed, weights of 20 tablets at 5 minutes of compression were recorded, and the data are presented in Table 38.

Table 38 Press Speed (TPM) Tablet Weight Range (mg) Difference (mg) 1000 198-202 4 2500 197-203 6 4000 198-203 5 6000 197-204 7 9000 194-206 12 12000 193-107 14


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Press Speed vs Weight Difference

02468

10121416

0 2000 4000 6000 8000 10000 12000 14000

Press Speed (TPM)

Wei

ght D

iffer

ence

(mg)

Figure 15 Press Speed versus Weight Difference

Based upon the tablet weight range target of 194-206 mg (±3 %), the press speed range was specified at 1000-7000 TPM. Based upon the studies summarized above, following in-process limits are being proposed for the ACE Tablets, 20 mg (Table 39).

Table 39 Proposed Limits Test Limits Comments Individual Weight Variation

200 mg ± 3.0% Discussed above.

Weight of 20 Tablets 4.00 g ± 3.0% Discussed above. Hardness 4.4-9.5 kP Discussed above Friability

NMT 1.0 %

Based upon actual data. Controlled by compression force, which is correlated with hardness.

Based on process understanding and risk assessment (utilizing FMEA), compression was predicted to be a critical step in the manufacture of acetriptan tablets. Compression force was identified as a critical process parameter, because of its significant impact on the critical quality attribute of dissolution if not adequately controlled. Pre-compression force and press speed are included in some of the models to get a better statistical fit, however their contributions are not significant within the ranges studied (0.5-3.0 kN,1000-7000 TPM) . The compression force required to obtain particular tablet hardness can be influenced by a number of factors including properties of the blend and equipment parameters, therefore the compression force required to produce tablets with the required hardness could vary from batch to batch and from machine to machine. The equipment parameters are established by controlling the target output attributes for compression, the output attributes are monitored and controlled by in-process measurements,


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The results of the compression DoE were used to define the process output attributes for compression presented in Table 39. The lower limit of the hardness is based on handling studies and acceptable friability results. The upper hardness limit is based on achieving acceptable dissolution of 80% at the 30 minute time point. During batch set-up the compression force is set at a value that produces tablets which exhibit the target attributes as indicated by the in process measurements. Once the appropriate compression force is established, it is controlled within specified limits by a feedback control loop.

2.3.1.4 .3 Study ProcDev-4: Effect of Inputs to Compression Step Based on previous experience with similar formulations, the following responses (which include both intermediate and final product attributes) were measured to assess the impact of varying input materials and process parameters during the roller compaction and milling steps (Table 40): The material inputs to this study were obtained from the DOE on the roller compaction step (Study ProcDev-2).

Table 40 Input Variables

In-process Product Attributes Compression Process Parameters

Final Product Attributes

Ribbon density Granule size distribution Granule uniformity

Precompression force Compression force Press speed Feeder speed Feeder fill depth

Tablet weight Tablet weight uniformity Tablet hardness Tablet friability Tablet disintegration time Tablet dissolution rate Tablet uniformity of content

A series of multivariate analyses, including DoE, was undertaken to investigate the relationship between the input attributes, compression process parameters and output attributes.

Table 41 Results

Parameter Target Low High Hardness (Average of 20 Tablets) 8 kP 5 kP 11 kP Weight (Average of 20 Tablets) 200 mg 194 mg 206 mg Individual core weights 200 mg 190 mg 210 mg

A DoE study was undertaken to assess the impact of variable inputs on the compression process. The upper and lower level of each variable was chosen to bracket the expected range of process inputs (identified from optimization of the formulation and previous process stages) and target tableting process parameters. The input variables and process parameter ranges investigated are given in Table 42. The experiments were performed on a rotary tablet press.


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Table 42 DoE Compression Inputs

Input Variables and Compression Process Parameters

Lower Upper

Relative ribbon density 0.68 0.81 Granule GSD (d50 µm) 250 500 Granule Uniformity (%) 2 5 Hardness (kN) 5 11 Press Speed (tablets per min) 1,000 7,000 Precompression Force (kN) 0.3 2.9 Compression Force (kN) As required to achieve hardness limits All of these variations reflect the likely variability of inputs that will be experienced during routine manufacture of ACE tablets. The impact of the variable inputs and process parameters on tablet weight, friability, disintegration time, and dissolution was determined. All tablets produced met the acceptable ranges for the critical product attributes defined in the quality target product profile. Batches of ribbon that exhibit densities towards the lower end of the acceptable specification range require pre-compression forces and compression forces towards the upper end of the ranges described below.

Table 43 Tableting Parameters Optimized for Ribbon Density Compression Process Parameters

Relative Ribbon Density 0.68-0.75

Relative Ribbon Density 0.75-0.81

Pre-compression Force (kN) 1.0-2.9 0.3-2.0 Compression Force (kN) 9.0-13.5 6.8-11.0 Press Speed (tpm) 1000-7000 1000-7000 Feeder Speed (rpm) 10-18 10-18


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2.3.1.4 .4 Critical Process Parameters for Tablet Compression

Table 44 Tablet Compression Process Parameters Input Criticality Control Strategy

Material Attributes Drug Substance Particle Size Not Critical See Blending Lactose Particle Size Not Critical See Blending MCC Particle Size Not Critical See Blending Ribbon density Critical PAR: 0.68-0.81 Granule size distribution Demonstrated Not Critical PAR: 100-200 Granule uniformity Demonstrated Not Critical PAR: < 5% RSD

Process Parameters Press Geometry Not Critical Fixed Tooling Geometry Not Critical Fixed Feeder Speed Not Critical PAR: 10-18 rpm Feeder Fill Depth Not Critical PAR: 15-20 mm Pre-Compression Force Demonstrated Not Critical PAR: 0.5-3.0 kN

Controlled based on Ribbon Density

Compression Force Critical PAR: 6.8-13.5 kN Controlled based on Ribbon Density

Ejection Force Not Critical Monitored

Press Speed Demonstrated Not Critical PAR: 1000-7000 TPM Height of Finished Tablets Drop Not Critical

2.3.2 Scale Up

2.3.2.1 Scale Up of the Blending Process The above described pharmaceutical development work on blending operation was carried out on a 1.5 kg batch in a 5 L capacity twin shell blender. To scale up to the 150 L blender used for the exhibit batch, the following scale up rules provided initial estimates of process parameters on the larger scale:

• Geometric similarity: keeping the ratio of all lengths constant (constant fill ratio) • Dynamic similarity: maintaining constant forces (Froude number Fr)

o g

RRPMFr

2

= 3 VR ≈

o RPM: rotation rate, R characteristic radius, g gravitational constant • Kinematic similarity: maintaining a consistent number of revolutions (RPM x time)

On the exhibit batch scale, the fill ratio was maintained same as the development work while the RPM and mixing time were estimated from the scale up rules. To verify the scale up, two runs from the pilot scale development study were replicated on exhibit batch scale. They represented the extremes of the factors chosen. On the pilot scale BU measurements by NIR were collected until 60 minutes with the reported BU RSD response obtained at 40 minutes. On the exhibit scale BU was measured until 100 minutes with the reported BU RSD response obtained at 70 minutes


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with no improvement on further mixing. BU RSD is the blend uniformity after blending and before roller compaction. GU RSD is the granule uniformity after the milling step.

Table 45 Pilot scale runs used in scale up evaluation Number A (MCC) B (DS) C(Lactose) Response (BU RSD) Response (GU RSD)

5 0 (75) 0 (30) 0(80) 4.8 1.8

Table 46 Exhibit scale runs used in scale up evaluation Number A (MCC) B (DS) C(Lactose) Response (BU RSD) Response (GU RSD)

E5A 0 (75) 0 (30) 0(80) 5.0 2.0 E5B 0 (75) 0 (30) 0(80) 4.6 1.6

In the production of the bio-batch, the mixing speed was kept at 8 rpm (equipment constraint) and the run time (50 minutes) was determined by reaching a NIR BU target of less than 6.5% RSD for ten consecutive revolutions. These scale up rules will be used to provide initial estimates of process parameters in the proposed commercial process (subject to verification).

Table 47 Scale Up Results Scale

Amount (kg)

Blender Capacity (L)

Mixing Speed (rpm)

Volume Fill Ratio

Run Time (min)

Run Response Blend Uniformity Before Compaction (RSD)

Response Granule Uniformity After Lubrication (RSD)

Pilot 1.5 kg (7.5 k units)

5 16

67 % 40

5

4.8%

1.8%

Exhibit 50 kg (250 k units)

150 8 8 8

67% 70 70 50

E5a E5b Bio

5.0 % 4.6% 4.7%

2.0% 1.6% 1.5%

Commercial (estimated)

150 kg (750 k units)

500 8 67% Est 60 (max 90)

Batch sizes are given in terms of total material (a slightly smaller fraction, 97%, of the material is blended

2.3.2.2 Scale Up of the Roller Compaction Process Roller compaction development was conducted at values representative of the full-scale process. Scale up will be accomplished by extending the process time.

2.3.2.3 Scale Up of Lubrication Process A similar lubrication time will be used on exhibit and commercial scale.


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Scale Amount (kg) Blender Capacity

(L)

Mixing Speed (rpm)

Volume Fill Ratio

Run Time (min)

Number of

Rotations Pilot 1.5 kg

(7.5 k units) 5 16

67 % 2-5 32-80

Exhibit 50 kg (250 k units)

150 8 67% 5 40

Commercial (estimated)

150 kg (750 k units)

500 8 67% 5 40

2.3.2.4 Scale Up of the Tableting Process Tablet presses were run at the speeds to be used in commercial production during development and production of the exhibit batch. Additional throughput will be added by using additional presses.

2.3.3 Control Strategy Note to Reader: A QbD application will contain a control strategy that provides an integrated overview of how quality is assured. The control strategy indicates how raw material specifications, process operating parameters, in-process tests and end product testing work together. If there is a better understanding of how raw material variation and process parameters can be control to ensure quality then there is the possibility of reduced product testing. This example contains a control strategy element of blending to a uniformity endpoint. Industry comments suggest that the current practice is blending to a fixed time and then accepting or rejecting the batch. In this example, use of a PAT tool is illustrated to determine the endpoint which meets the quality requirement for further processing. Based on the understanding of process conditions in this example, there is a proposal for reduced end-product testing. This is an example of how to propose reduce end-product testing and it should not be interpreted that this proposal would be accepted by FDA. The control strategy is the combination input material controls, process controls and monitoring, design spaces around individual or multiple unit operations, and final product specifications used to ensure consistent quality. For this product our control strategy for the proposed commercial scale process is in Table 48. In this table, the different elements of the control strategy are indicated in the third column. Operating ranges for the critical process parameters are contingent on scale up and validation. Specification and in-process controls are regulatory commitments for the proposed commercial process.


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Table 48 Control Strategy Attribute or Parameter Range Type of Control

Input Material Attributes DS Polymorphic Form (Melting Point)

110-115C DS specification

DS particle size (d90) 25-35 µm DS specification DS particle size (d50) 10- 20 μm DS specification DS particle size (d10) 1-10 μm DS specification MCC (d50) 50 – 100 µm Excipient specification Lactose (d50) 70 – 100 µm Excipient specification

Blending Mixing Speed 8 rpm Operating range Number of Rotations Blend to BU endpoint of 6.5%

RSD Online PAT endpoint

Blend Uniformity NMT 6.5% In-process control Roller Compaction and Milling

Roll Pressure 75-150 bar Operating range Mill Screen Size 1.0 to 2.0 mm Operating range Granule Size Distribution (d50) 250 -500 µm In-process control Relative Ribbon Density 0.68-0.81 In-process control

Granule Lubrication (Final Blend) Blend Time 5 minutes Operating range Granule Uniformity NMT 5.0% In-process control

Tablet Compression Pre-compression Force (kN) 0.3-2.9 Operating range Compression Force (kN) 6.8-13.5 Operating range Press Speed (tpm) 1000-7000 Operating range Feeder Speed (rpm) 10-18 Operating range Individual Weight Variation 200 mg ± 3.0% In-process control Weight of 20 Tablets 4.00 g ± 3.0% In-process control Hardness 4.4-9.5 kP In-process control

End Product Testing (Release) Dissolution NLT 80% at 30 mins, pH 1.2

2% SLS, 75 rpm Release specification

Identity (IR)* Positive Release specification Assay 95.0% – 105.0% of label

claim Release specification

Content Uniformity* AV < 15 Release specification Impurity ACE12345 NMT 0.5%,

other impurities NMT 0.2%, total degradation products NMT 1%

Release specification

Description White to off-white, round unilaterally convex tablets embossed with GEN-ACE and 20

Release specification

Friability* NMT 1.0% Release specification * These tests are proposed for removal after the commercial process is established. See 2.3.3.5.

The drug substance particle size limits arise from a combination of its impact on blending, in vitro dissolution and in vivo performance. The blending study sets the lower limit of 25 µm, while the in vitro dissolution was acceptable with the 30 µm but not with the 45 µm d90. Although the in vivo study with 45 µm d90 was acceptable, we set an upper limit of 35 µm which


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will ensure that the in vitro dissolution is easily met. Limits for d10 and d50 represent characteristics of the material used to manufacture the exhibit batch. Excipient and drug substance particle size impacted content uniformity through the mixing and blending step prior to roller compaction. Excipient particle size specifications were based on the attributes of the selected grades. We have evaluated many batches from these suppliers for other products and found consistent particle size distributions and thus we use limits on d50. These limits were justified based on the development studies that showed that the critical quality attributes were robust with respect to changes in excipient grade. Based on process understanding and risk assessment, blend content uniformity is the attribute that influences content uniformity. Uniformity of the blend and blending end-point is monitored by NIR. The blend operation will be terminated when blend uniformity is first achieved, to avoid segregation. Based on the analysis of dissolution data collected and the results of pilot in vivo studies, the 1% SLS media used in product development and the QTPP was more sensitive to product differences, but the 2% SLS media gave a better correlation with in vivo bioequivalence (1% SLS was over discriminatory). For this reason, the 2% media is used as the release specification in the control strategy. In product development work the unit operations with high risks were addressed. Experimental studies were then defined and executed to develop additional scientific knowledge and understanding, to allow appropriate controls to be developed and implemented thereby mitigating the risk to quality. After detailed experimentation, the initial overall risk assessment updated in line with the process understanding obtained is given below

Table 49 Application of Control Strategy to Mitigate Identified Risks in Process Parameters

Low risk based on prior knowledge Control Strategy applied to high risk to mitigate risk High risk

Variable and Unit Operations

DP CQA Pharmacy Blending Roller Compaction

Milling Final Lubrication

Compression

Assay Controlled by weight

Low Low Low Low Controlled by tablet weight

Impurities Low Low Low Low Low Low

Content Uniformity

Low Controlled by

Mixing time and

speed

Controlled by by granule properties

Controlled by granule properties

Low Controlled by tablet weight

and appropriate feed settings

Dissolution Low Low Controlled by ribbon density

Controlled by

granule properties

Low Controlled by tablet hardness


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2.3.3.1 Control Strategy for Blending A risk matrix table for the blending operation demonstrates that the identified risk to the quality attributes has been mitigated by control of acetriptan, lactose and MCC particle size and monitoring of blend uniformity. A near IR online tool for monitoring the blend uniformity was developed and is used to terminate the blending when sufficient uniformity is reached.

2.3.3.2 Control Strategy for Roller Compaction and Milling The intent of the control strategy for roller compaction is to maintain the ribbon density within the required range to ensure drug product of appropriate product quality can be produced. To maintain a ribbon density of 0.68 to 0.81 during routine operation, the compression pressure will be controlled. The ribbon density will be monitored and deviations from the target are used for adjusting the compaction force. For milling, the mill screen size and speed will be selected to ensure that the granule size distribution remains within the proven range (250-500 µm). For the initial process, mill screen size and speed will be selected to ensure that GSD will remain within the proven ranges. If a change to the mill is made e.g. scale-up or down, then the impact on granule size distribution (and assay of sieve fractions) will be assessed across the pre-defined ribbon density range. No routine in-process test for fines is included in the control strategy. Changes to the mill screen or impeller speed may be required at this stage to ensure that granules manufactured during future routine operation fall within the proven GSD ranges across the defined ribbon density.

2.3.3.3 Control Strategy for Lubrication The control strategy for lubrication step is based on the impact of lubrication time on the CQA of the tablets. Based on our experimental trials, it was determined to mix for set number of revolutions at a set speed as given in the scale up section. Notes: The purpose of the lubrication step is to ensure the milled material runs smoothly on the compression machine. There is a specified order of addition for the talc and magnesium stearate. The product is blended using a diffusion mixer for a targeted number of revolutions (e.g. 40 revolutions).

2.3.3.4 Control Strategy for Tablet Compression The control strategy for compression is to maintain the tablet attributes of hardness and tablet weight within the required ranges. The target compression force required to produce tablets with acceptable quality attributes is established using the in process measurements at the beginning of the run. After tablets with target weight and hardness are obtained as part of the compressing machine set-up, the upper punch penetration depth and the fill volume are fixed and this sets the target compression force. The compression force is continuously measured throughout the run for each tablet and compared to the target compression force. Deviation from the target is


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measured automatically by the online system and provides feedback for adjusting the fill depth. Upper and lower limits of compression force are set and any tablet that registers a compression force outside these limits is automatically rejected by the tablet press.

2.3.3.5 Reduced Release Testing The elements of the control strategy indicated as release tests with a (*) will not be conducted after the process is established. Once the commercial scale process is validated (including challenges of the ranges included in the control strategy) and demonstrated to be operating consistently in commercial production (N batches), these test will be removed from the control strategy following appropriate notification to the FDA.

3.1 Development Conclusions After process development, the quantitative formulation composition remained the same as the end of formulation development. The grades of the excipients, as a function of particle size distribution, were selected based on the process development and they are included below.

Test Product Grade

Ingredient Function Weight/tablet % (w/w) Acetriptan, USP Active 20.00 mg 10 D90 25-35 µm, d50 10-20 µm, d10 1-

1-10 µm Intragranular Excipients

Lactose Monohydrate, NF Filler 43 mg 21.5 Grade A (d50, 70 – 100 µm) Microcrystalline Cellulose, NF Filler 120.0 mg 60.00 Grade A (d50, 50 – 100 µm) Croscarmellose Sodium, NF Disintegrant 6 mg 3 Talc, NF Glidant/Lubricant 5 mg 2.5

Extragranular Excipients Magnesium Stearate, NF Lubricant 1 mg 0.5 Talc, NF Glidant/Lubricant 5 mg 2.5 Total Weight 200.0 mg 100%


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Abbreviations Used in this Document: API: Active Pharmaceutical Ingredient AUC: Area Under the Curve CMA: Critical Material Attribute Cmax: Concentration Maximum CPP: Critical Process Parameter DOE: Design of Experiments DS: Drug Substance FMEA: Failure Mode and Effect Analysis GSD: Granule Size Distribution LOD: Loss on Drying MA: Material Attribute PP: Process Parameter PAR: Proven Acceptable Range PSD: Particle Size Distribution QTPP: Quality Target Product Profile RLD: Reference Listed Drug (Product) Tmax: Time for achieving Maximum Plasma Concentration

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