A Regulatory Perspective In Pharmaceutical Industry

Published Date: 02 Nov 2017

After evaluation of cGMP in twenty-first century by FDA in pharmaceutical, the concept of Quality by Design (QbD) has been originated as a key point of success in pharmaceutical development. Quality by Design produces the design, formulation development, manufacturing processes which assures predefined product quality specification[1]. This initiative approach establish a new framework of regulatory authority and leads the modernization of FDA’s regulation for pharmaceutical quality. An important part of QbD is to understand how any process and formulation parameters affect the product characteristic and how there optimization should be identified in order to monitor and specify these parameters for production process in desired quality state of product. Recently pharmaceutical industries are going through a major changes like;

Increasing demand about efficiency of work

Increased drug prices

Market Specification and commercial aspects

R & D criteria and developing risk

Growing Regulatory specification

QbD create complete positive and successive approach towards these facts of industry’s of drug product development and manufacturing process. QbD defines many elements like; Critical Quality Attributes(CQAs), Critical Process Parameter(CPP), Control Strategy Design space, Target Product Quality Profile(TPQP), and Continuous improvement in the products from R&D to production and then to market. The Concept of QbD was mentioned in the ICH Q8 guidance which states that; "Quality cannot be tested into products i.e., Quality should be built in products by Design."[2].

The main aim and objective of QbD are;

To evaluate the basics of current industrial and regulatory approach for the submission into the NDAs by using QbD.

To evaluate criteria quality aspects which affect industry facility.

To know how QbD is used to establish specification for drug product and its commercialization, various operation in the industry and availability.

To establish a quality pharmaceutical sector.

DETERMINATION OF PHARMACEUTICAL QALITY BY TRADITIONAL WAY (BY TESTING)

Figure 1 shows that the quality of generic drug products by testing i.e. by traditional approach.. in this test quality is assured by testing raw material, API characteristic, manufacturing process, and there after finally finished drug products. If quality of excipients, API not meet to the said criteria of quality specification then the finished products are discarded. After unit operations and manufacturing process also, drug products not meet specification then also finished products are discarded.

In Process Specification

Finished Product Specification

Product meeting QUALITY

If Fails,

Material Discarded

Unit operations with fixed process parameters

If fails, Product Discarded.

Excipients meeting specification

FIGURE 1: A simplified quality control diagram using QbT.

This combination of various steps of manufacturing and there testing was used for quality check in quality by testing approach. but, in this case there was limited scope for variability identification, CQA, CPP and it causes imperfect evaluation of quality specification towards both drug products and consumer safety[3,4].

DETERMINATION OF PHARMACEUTICAL QUALITY BY QBD APPROACH

ICH Q8 guideline [5]. defines quality of the products as "The suitability of a drug substance or drug product for its specified use. These include parameters likes identity purity and strength." ICH Q6A [6]. evaluate the key role of these specification which states that "these Specification are critical quality standards which are put forward and justified by regulatory and manufacturing authority. QbD is defined as "systematic, scientific, risk based, novel approach to pharmaceutical development which begins with the prespecified objectives and evaluates the processes, products and there control[7]. which means designing and developing of formulation and manufacturing process to ensure priorly known product quality[3]. QbD identifies those characteristics which are critical with respect to quality of the patient and also drug product efficacy and then creates new aspects of desired quality for both patient and product point of view[8]. This information of critical process parameters is then used to originate novel flexible and quality manufacturing process which leads to production of reproducible quality products over time of periods: various elements which are included in QbD are,

Target Product Quality Profile(TPQP)

Designing and developing product and manufacturing processes

Identification of critical quality attributes

Control of manufacturing processes to produce consistent drug products quality over time.

In Process Specification

Finished Product Specification

Product QUALITY

Acceptance criteria based on performance. Testing may not be necessary to release batches

Unit operations with fixed process parameters

If Fails,

Understanding and fixing root cause

Excipients meeting specification

CONFIRMS QUALITY SHOULD ALWAYS MEET

FIGURE 2: A Simplified quality assurance diagram under QbD.

COMPARISON BETWEEN CURRENT STATE AND DESIRED QBD STATE.

TABLE 1: Shows comparison between current state of quality and desired QbD state.

Parameter

Current States

Desired QbD State

Pharmaceutical development

Empirical, typically univariate experiment

Systematic, multivariate experiments

Manufacturing process

Locked down validation on three batches , focus on reproducibility

Adjustable within design space, continuous verification with design space, focus on control strategy

Process control

In-process testing for go/no-go, offline analysis .

PAT utilized for feedback and feed forward in real time

Product specification

Primary mean of quality control, based on batch data

Part of overall quality control strategy, based on product performance

Control strategy

Mainly by intermediate and end product testing

Risk based control shifted up steam, real- time release

Lifecycle management

Reactive to problems and OOS post approval changes needed

Continual improvement enabled within design space

CHARACTERISTICS OF AN IDEAL QBD

Includes product design and process development specification

Scientific approach and Risk based analysis

Major aim is of is patient safety and product efficiency

Increase in Business benefits

Results in increased process understanding and knowledge

Results in improved process capability

Systematic development Approach

Novel concept of development

Evaluates Multivariate’s- interaction

GENERICS QBD PRINCIPLES

Target product quality profile

AIM and OBJECTIVE

Understand attributes of

Physicochemical and Biopharmaceutical properties of drug.

the formulation and manufacturing

process that have potential

to change the BIOAVAILABILITY

of a particular active ingredient.

Extensive formulation and manufacturing experience for many generic manufacturers

FIGURE 3: Simplified Diagram showing generic QbD principles

Various points regarding to this process are about Drug Substance, Excipients, process and then characteristic of finished drug products.

ICH Q8, Q9, Q10: THE FOUNDER OF QBD

Desired State: QbD

FIGURE 4: Diagram showing that ICH Q8, Q9, Q10 is the base of QbD origination

The concept of QbD has been given in the ICH guideline Q8. Then the pharmaceutical development is assessed by finding Critical Quality Attributes like API characteristic (polymorphism, particle size, stability), Excipients (polymers to control release, compatibility). ICH guideline Q9 assess the risk management status of these processes. ICH Q10 then finally manages the quality system in all aspects.

STEPS INVOLVED IN QBD IMPLEMENTATION

IDENTIFICATION OF TPQP

IDENTIFICATION OF CQA

RISK ASSESSMENT

DEFINE PRODUCT

DESIGN SPACE

RISK ASSESSMENT

DEFINE PROCESS DESIGN SPACE

PRODUCT CHARACTERIZATION

DESIGN OF EXPERIMENT

REFINE PRODUCT DESIGN SPACE

DEFINE CONTROL STRATEGY

REGULATORY FILING

PROCESS VALIDATION

RISK ASSESSMENTꜜ

PROCESS MONITORING

FIGURE 5: Major steps in the implementation of QbD approach for a pharmaceutical product.

IDENTIFICATION OF TARGET PRODUCT QUALITY PROFILE (TPQP)

The Target Product Quality Profile (TPQP) has been defined as a "prospective, specific and randomized summery of qualitative parameters of a drug product that successively will be achieved to ensure the desired product is generated" [9]. This involves drug dosage form and its route of administration, strength(s) of dosage form , therapeutic drug release and pharmacokinetic characteristic (e.g. Dissolution) of the drug product dosage form[10]. TPQP is the quality parameter of the drug product that should have reproducibility in producing therapeutic effects. The TPQP guides formulation scientists for establishment of formulation strategy in such a way that the produced product should be efficient. Ultimately TPQP is related to the overall quality characteristic of drug products like assay, dosage form, identity, purity and Stability [11].

IDENTIFICATION OF CQAS

After determination of TPQP the appropriate CQAs are identified. CQA has been defined as "a physicochemical, Biological property or all characteristic that should be within specified limit, range to ensure desired quality of drug product."[12]. CQAs is identified by examining Risk Assessment as per ICH Q9 guidance (Fig.4,5) prior product knowledge and product specification with specific Quality product attribute perform the key role in risk assessments. This information provides a rationale relating the CQA to product safety and efficacy. Use of robust risk assessment methods for identification of CQAs is novel to the QbD paradigm.

DEFINING DESIGN PRODUCT AND PRODUCT DESIGN SPACE

Determination of CQAs identifies the product design and design space (i.e. specification for in-process quality check, API and drug product quality specification). These specification are generated on the basis of attributes to the safety and efficacy of the products. These specification are not limited to the process ability related to the manufacturing batches, design space, clinical and nonclinical studies with similar products. Basically the difference obtained between the clinical studies and set quality specifications completely depend on the information gained about CQAs under consideration of product safety and efficacy of desired drug products. QbD approach relates various studies approach and then link them for realization of improved efficacy by increasing knowledge about analytical, clinical and nonclinical studies. By this way the biopharmaceutical characteristics of drug substances are taken into consideration by formulation scientist [13]. Table 2 represent, how BCS classification system helps in drug product development process and what are the impacts on physicochemical and Biopharmaceutical characteristic of drug products [14-16].

TABLE 2: Impact of biopharmaceutical classification system on formulation of dosage form design.

Classification

Impact on formulation of dosage form design.

Class I

High Solubility

High Permeability

No major challenges for immediate release dosage form

Controlled release dosage form may be needed to limit rapid absorption profile

Class II

Low Solubility

High Permeability

Formulation design to overcome dissolution rate profile:

Particle Size Reduction

Salt Formation

Precipitation Inhibitor

Metastable Form

Solid Dispersion

Complexation

Lipid Technologies

Class III

High Solubility

Low Permeability

Approaches to improve Permeability:

Prodrugs

Permeation Enhancer

Ion Pairing

Bioadhesives

Class IV

Low Solubility

Low Permeability

Formulation has to use combination of class II and class III to overcome Dissolution and Permeability problems for oral administration.

Use alternative routes like IV.

Class V

Variable Solubility

Variable Permeability

(Metabolically Unstabled Compounds)

Approaches to avoid instability:

Prodrugs

Enteric Coating

Enzyme Inhibitor

Lymphatic Delivery (to avoid Ist pass metabolism)

DEFINING PROCESS DESIGN AND PROCESS DESIGN SPACE

Product is incomplete without process hence these two terminologies are not separated as different one. Process design is initial and primary step of process design in product development from small scale to commercialized scale. This includes all parameters of process development like equipments, facilities, material transfer; manufacturing aspects of variation [17]. In a continuous operation process of development CPP have the largest impact as these are main process input variables. Table 2 lists the critical process parameter for manufacturing of ophthalmic solution and quality attributes. Process reproducibility i.e. process robust is defined as, "capability of a process which produces the desired quality, performance and minimizes variations of input variables"[18]. Process Capability should be studied for assessment of consistency and reproducibility. Process capability index is nothing but, a statical measurement of process variability for specified parameters. Mostly accepted formula for CpK is based on six sigma principle.

Process Capability = Upper specification limit – Lower specification limit

Index (CpK) 6 standard deviation

If the value of CpK is greater than 1 then the process is considered as capable process. If it is low then five step procedure is given by Rath and Strong [19]. to reduce the process variability. Which are:

STEP I: Define- clearly states the intended improvements

STEP II: Measure- measurement of critical product performance attributes to check whether they are out of specified limit and used for said sigma level of process

STEP III: Analyze-When sigma level is below the target, then steps for assessment increases starting by defining most accessible cause of variation.

STEP IV: Improve- The process must be redefined and redesigned and causes of variance should be eliminated by incorporating process Controls.

STEP V: Control- Evaluation and maintenance of improved manufacturing process done for control specification.

Design of experiment perform key role in determining the relationship amongst the factors which affects process output. The complete approach towards characterization of process includes 3 steps, first risk assessment by identifying process parameters, second design of study by using DoE. On the basis of these two Design space is identified and defined. Third, these studies are evaluated for determining the necessity of CPP in development of design space.

TABLE 3: Shows Product Development Workflow for Ophthalmic solution dosage form.

Potential Quality Attributes

Stable Ophthalmic Product with Consistent Drop Size

Physicochemical

API compatibility

Viscosity change

Mass transfer

Dose Delivery

Dropper tip Size

Product Viscosity

Drop Size

Material

Polymer Grade

Container additives

API Characteristic

Process

Thermal Sterilization

Polymer Concentration

Filtration

Management

Communication of CQA’s

Communication of CPP’s

Design Space Definition

Personnel Control

Compounding/blend of 2 bulks

Sterilization Process Control

Aseptic operations

DETERMINE THE CONTROL STRATEGY

It can be defined as "A preplanned set of quality control which is obtained by product and process information which helps in assuring the Process performance along with Product Quality"[20]. In the QbD system the control strategy is developed by major two factors which are Risk Assessment which take into consideration of CQAs and CpK. The control strategy is developed mainly on, Batches release testing, IPQC, Process Control, Stability testing, etc. But Risk Assessment is the basic for developing control strategy in QbD.

PROCESS VALIDATION AND REGULATORY FILING

The evaluated process of manufacturing and redefined process design space causes flexibility in manufacturing process in process validation [21, 22]. Assurity of quality by process design space and product quality generates significant acceptance criteria in validation. Because of Process design space the quality products obtained, also it creates small pilot models for manufacturing scale process. Hence in QbD approach process design space plays key role in validation Criteria. In regulatory filling along with process design space, product design space specification, control strategy explanation, validation data, process monitoring plan set required. In QbD system, the filling includes some prootocols like comparability and change prootocol, which allow in process change criteria for improving flexibility of system which may be going to agreed by agencies and applicants in future.

PROCESS MONITORING

In QbD system process changes in process design space not need any approval and review [23]. Hence, improvements in process during life cycle of product take place with post approval submission along with process consistency. It leads to improved understanding of risk assessment related to the effects on changes in the process and manufacturing variations on the quality of product [24]. Robustness in QbD has to provide all aspects of all specification like Process and Product performance, Management, preventive measurements. Thus, QbD approach requires an adequate estimation of changes occurred which are not shown by regulatory approvals [21].

FUTURE SCOPE

In a complete lifecycle of a product, manufacturing processes are assessed and monitored for ensuring the working standards which are obtained or not for desired product quality attributes. Process capability and Process stability are measured and evaluated, if it leads to determination of any undesired process variability, significant actions will be taken to modify, to correct, and to prevent future problems so that the process should be in control. The additional information gained about routine manufacturing operations and processes will be utilized as alternative or as a adjustment tool for process parameters as part of the continuous improvement of quality drug products. As a result, the regulatory authorities will be notified in accordance with CFR 314.70 relating each and every changes observed in each condition beyond the variability provided in application [21].

CONCLUSION

After implementing cGMP, The Office of Generic drug utilizes the concept of QbD for drug filling to ANDA by the way of Questions Based Review (QBR) approach. Today the acceptance toward strategy of QbD increasing fastly for commercialization and to improve business position in the generic industry competitive. The ideal and successful approach of QbD is filing to ANDA in generics. QbD itself is playing role as a guide, for product and process development along with establishes a smooth and easy pathway for scale up, technology transfer. In all considered criteria QbD is going to become a major tool in all companies.