Pharmaceutical Development As Per ICH Guidelines

INTRODUCTION

The Pharmaceutical Development section provides an opportunity to present the knowledge gained through the application of scientific approaches and quality risk management to the development of a product and its manufacturing process. It is first produced for the original marketing application and can be updated to support new knowledge gained over the lifecycle of a product. The Pharmaceutical Development section is intended to provide a comprehensive understanding of the product and manufacturing process for reviewers and inspectors. The guideline also indicates areas where the demonstration of greater understanding of pharmaceutical and manufacturing sciences can create a basis for flexible regulatory approaches. The degree of regulatory flexibility is predicated on the level of relevant scientific knowledge provided.

PHARMACEUTICAL DEVELOPMENT

The aim of pharmaceutical development is to design a quality product and its the manufacturing process to consistently deliver the intended performance of the product. The information and knowledge gained from pharmaceutical development studies and manufacturing experience provide scientific understanding to support the establishment of the design space, specifications, and manufacturing controls.

Information from pharmaceutical development studies can be a basis for quality risk management. It is important to recognize that quality cannot be tested into products; i.e., quality should be built in by design. Changes in formulation and manufacturing processes during development and lifecycle management should be looked upon as opportunities to gain additional knowledge and further support the establishment of the design space. Similarly, the inclusion of relevant knowledge gained from experiments giving unexpected results can also be useful. Design space is proposed by the applicant and is subject to regulatory assessment and approval. Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post approval change process.

The Pharmaceutical Development section should describe the knowledge that establishes that the type of dosage form selected and the formulation proposed are suitable for the intended use. This section should include sufficient information in each part to provide an understanding of the development of the drug product and its manufacturing process. Summary tables and graphs are encouraged where they add clarity and facilitate a review.

At a minimum, those aspects of drug substances, excipients, container closure systems, and manufacturing processes that are critical to product quality should be determined and control strategies justified. Critical formulation attributes and process parameters are generally identified through an assessment of the extent to which their variation can have an impact on the quality of the drug product.

Post-Notice of Compliance (NOC) Changes

Introduction:

Following are the reasons for Post NOC changes:

·         To improve the quality of the drug.

·         To improve the efficiency of the manufacturing process.

·         To solve marketing issues.

·         Changes in the labeling of the drug for “warning” or managing the “risk factors” or limiting the “targeted population” or limiting the “dosage”.

These drugs may include pharmaceuticals, biologics, and radiopharmaceuticals for human use and pharmaceutical, radiopharmaceutical and certain biotechnological products for veterinary use.

Health Canada recognizes that:

·         any change to a drug may impact the safety, efficacy and quality of that drug and;

·         any change to the information associated with the drug (for example [e.g.], labeling) may impact the safe and effective use of that drug.

To manage the safety and risks of the public in using the drugs and foods, there are certain rules and regulations administered by “Health Canada”.

One important area of these regulations are administrative rules managing the “Post Notice of Compliance” (Post NOC) related to a drug.

Post NOC provides sponsors with recommendations on the data required to enable Health Canada to make an accurate determination of the impact of a change on the safety, efficacy and quality of the new drug.

Level of changes to a drug and subsequent obligations of the sponsor are as followings Levels:

ü  Supplements. (Data should be submitted to Health Canada for review prior to implementation.)

ü  Notifiable Changes. (Data should be submitted to Health Canada for review prior to implementation.)

ü  Annual Notifications. (Data should not be submitted but should be available to health Canada upon request)

ü  Record of Changes. (Data should be retained by sponsor)

Reporting Categories:

Level I – Supplements:

These changes to a new drug are “significantly different” as it relates to the matters specified in C.08.003 (2) of the Food and Drug Regulations and have the potential to impact the safety, efficacy, quality and/or effective use of the drug.

The changes included in this reporting category shall be filed, along with the recommended supporting data, to Health Canada as a Supplemental New Drug Submission (SNDS) or Supplemental Abbreviated New Drug Submission (SANDS).

The change may not be implemented by the sponsor until a NOC has been issued.

Guidance for changes to approved NDA or ANDA

FDA has published guidance to provide recommendations to holders of new drug applications (NDAs) and abbreviated new drug applications (ANDAs) who intend to make post-approval changes.

Reporting Categories:

There are four reporting categories which are distinguished in the following paragraphs:

A.   Major Change:

It is a change that has a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product as these factors may relate to the safety or effectiveness of the drug product.

It requires the submission of a supplement and approval by FDA prior to the distribution of the drug product made using the change. (Prior Approval Supplement)

B.   Moderate Change (CBE 30):

It is a change that has a moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product.

It requires the submission of a supplement to FDA at least 30 days before the distribution of the drug product made using the change. It is called Supplement - Changes Being Effected in 30 Days (CBE 30)

C.   Moderate Change (CBE 0):

It is a change that has a moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product.

It requires the submission of a supplement to FDA at the time of distribution of the drug product made using the change. It is called Supplement - Changes Being Effected (CBE 0)

Practical Tips for A Successful Pre-Approval Inspection (PAI) Outcome

Once an application is submitted, the firms and facilities mentioned are considered by FDA to be ready for inspection. 

The inspection team will determine if:

• the facility is prepared for commercial manufacturing

• the data submitted is according to site records

• the data submitted is complete and accurate

Readiness for Commercial Manufacture

The investigative team will determine whether your the firm contains a quality system that's designed to realize sufficient control over the ability and commercial manufacturing operations.

• Evaluate overall CGMP compliance because it relates to the applying product

• Evaluate the particular PAI product and process

- is that the facility adequate/qualified-building; equipment; water systems?

  - Will review the development Report.

• Will review batch records for submission batches (pivotal, qualification and/or bio batches)

• specialize in change control, deviations and trends regarding the event process to see that there's adequate evaluation

• Will evaluate sampling plans; testing of components and products

• High specialise in your supplier qualification program

• Evaluate facility and equipment procedures with a spotlight on contamination controls

• Specialise in laboratory system (SOPs; Personnel; Training) and stability data

• Evaluate test methods (validated?) and impurity profile

FDA’s Pre-Approval Inspection (PAI)

Facility Evaluation by FDA

Before approval, FDA evaluates the firm or facility by on-site inspections and/or by establishment file review when the firm is called within the Chemistry, Manufacturing, and Controls (CMC) section of a New Drug Application (NDA), Abbreviated New Drug Application (ANDA) or Biologic License Application (BLA)

Facility evaluations are conducted for:

– Finished dosage manufacturers

– API manufacturers

– Finished dosage and API testing sites

– Primary packaging and labeling sites

– For animal-derived APIs, the power that performs the crude extraction

FDA generally doesn't evaluate the subsequent sites for a pre-approval inspection:

Intermediate manufacturers

• On a case-by-case basis; evaluated on condition that the intermediate is taken into account critical to the standard of the drug product.

Exhibit batch manufacturers (if not proposed commercial site)

• Note: the positioning may be added on a for-cause basis if the review identifies concerns

Component manufacturers

• Includes syringes, glass vials, or rubber-stoppers manufacturers and component-only sterilization sites

• OPF/DIA generally doesn't evaluate these sites unless the for-cause basis

• it's the drug product manufacturer’s responsibility to qualify their suppliers.

Basics of 4 types of FDA Inspections

If you're a manufacturer or a processor of FDA-regulated products, you'll expect a visit from FDA. the aim of this visit is to verify compliance with all relevant regulations — most ordinarily stated as an “FDA inspection.”  But not all inspections are created equal.

FDA performs four kinds of inspections at many various kinds of facilities, and your company’s response should be tailored to the precise sort of event. Facilities that represent FDA’s watchful eye include:

ü  Drug manufacturers

ü  Device manufacturers

ü  Blood banks

ü  Food processing facilities

ü  Dairy farms

ü  Animal feed processors

ü  Compounding pharmacies relevant to your FDA inspects

ü  Facilities that conduct studies in people

ü  Laboratories that conduct studies in animals (support FDA approval of medical products)

FDA’s inspection authority also extends to foreign manufacturing and processing sites for FDA-regulated products sold within the US. Fall within these bounds, and you'll expect an FDA inspection at your facility.

The four differing kinds of inspections conducted by FDA are pre-approval inspection, routine inspection, compliance follow-up inspection, and “for cause” inspection.  Each is meant to assist protect the general public from unsafe products, but the main target and expectations of every sort of inspection are different.

Ø  Pre-Approval Inspections are conducted after an organization submits an application to FDA to market products for NDA or ANDA. These inspections target verifying data included within the application, and confirming that the firm is capable of producing said product. At the end of inspection inspectors will recommend for or against FDA approval.

Indian companies working on Covid-19 vaccines

Six Indian companies are working on a vaccine for COVID-19, joining global efforts to find a quick preventive for the deadly infection spreading rapidly across the world, says a top Indian scientist.
“While Zydus Cadila is working on two vaccines, Serum Institute, Biological E, Bharat Biotech, Indian Immunologicals, and Mynvax are developing one vaccine each,” Gagandeep Kang, executive director of the Translational Health Science and Technology Institute, Faridabad, told Press Trust of India.
“Vaccine development is a lengthy process which takes years, with many challenges,” said E. Sreekumar, chief scientific officer at the Rajiv Gandhi Centre for Biotechnology in Kerala.