Product License Maintenance

Requirements to undertake upon certification

Activities that a Product Licence/Marketing Authorisation maintenance holder is legally required to undertake once certificate is granted include (but is not limited to) the following:

• Regulatory impact assessment of change controls

• Licence maintenance through the submission of variations, supplements and renewals

• Regulatory compliance and conformance management to avoid registration drift

• Maintenance of a self-audit programme

• Post marketing surveillance, including pharmacovigilance (PV and QPPV) and the submission of Periodic Safety Update Reports (PSURs)

• Maintenance of post-approval and regulatory commitments

How InViva can help with Product Licence (PL) maintenance

InViva works with manufacturers to ensure product maintenance occurs seamlessly. InViva helps companies develop and implement schemes to attain excellence in all aspects of regulatory requirements, compliance  and conformance by providing full service support in all aspects of licence maintenance.

Our services include identifying areas of concern and risk, through to developing and implementing bespoke, sustainable solutions.

When Product Licence (PL) or Marketing Authorisation (MA) begins to drift away from the licensed details for the methods, processes, and controls used for the manufacture of an approved product. This is a phenomenon which if left unchecked can result in serious patient safety impacts.

Registration drift addresses product conformance and maintenance; there is a legal requirement to ensure the PL/MA continues to be aligned to the actual manufacturing details. This activity is typically undertaken by regulatory affairs.

Whilst being equally important, assurance of product compliance refers to compliance with quality requirements including cGMP and ICH conditions and is typically managed and controlled by the quality assurance (QA) group.

How can they be diagnosed?

Registration drift or product conformance may be easily diagnosed by answering some simple questions:

• Are your products more than 15 years old?

• Are your products manufactured by third parties under contract?

• Has your company been involved in merger and acquisition activities?

• Do you have high staff turnover and rely on “freelancers” and individual contractors to support your regulatory affairs department?

From InViva’s extensive experience in managing and resolving registration drift in over 10,000 MAs globally, specific sections of m3 CTD dossiers that are prone to registration drift have been identified. There are 24 key sections having been highlighted as most susceptible to conformance discrepancies.

To resolve registration drift a single consistent change control process that spans the full manufacturing, testing, and registration disciplines is critical. 

More information on the specific CTD sections and assessment and remediation are available by contacting us. 

How InViva can help with ??

InViva has developed a robust process for the identification and remediation of registration drift as a solution to product conformance issues,

Priorities products, collected MA, collate details in a single central location, and prepare to perform a Gap Analysis

Licence variations record the changes in methods of manufacture and testing that deviate from the originally approved methods and procedures. This approval can be in the form of a Marketing Authorisation (MA) or Product Licence (PL).

Variations record changes that result from amendments in legislation and regulatory requirements, or changes implemented by manufacturers as part of process improvements. Regardless of their source, all changes must to be submitted for assessment and approval by the relevant regulatory agencies, and in most cases, approval sought prior to distributing the “new” process.

Further details are provided below:

Post-marketing commitment

Following product approval, MAH have post-marketing commitments that ensure the MA is kept current and up-to-date and that changes to both the MA and Drug Master File (DMF) are notified. In particular, the risk of registration drift must be avoided through the robust implementation of a change control process.

Notification of changes to regulators must be through filing variations; this can be a complex and potentially time-consuming process, requiring careful consideration to ensure the commercial viability of a product is not impacted. 

Licence variation

A licence variation allows an amendment to the data previously approved by the regulatory authorities. Changes can have minimal or significant impact on the quality, safety, or efficacy of the medicinal product.

Licence variations are categorised on the severity of their impact:

Type IA: “Do and tell” – These are typically administrative changes whereby a manufacturer can make a change and then tells the authorities within 12 months. This is generally only applicable to minor changes in the manufacturing, testing, and release operation.

Type IB: “Tell and do” – These types of changes are also considered to be minor changes that require an assessment of supporting data as they may have an impact on product safety and efficacy. Manufacturers must notify the authority of a change before it is implemented.

Type II: “Tell and do” – These are major variations that manufacturers must submit to the regulatory authorities and obtain approval before implementing. These are usually major changes that are likely to have an effect of product safety and efficacy and will require careful assessment before approval.

Grouped variations – These variations are grouped and filed as one submission. This can only be done when there is a clear link between the changes. Depending on the type of variation, the changes need to be on the same MA or the change must be identical across several MAs.

In the USA, the FDA regulate similarly tiered amendments:

Annual Reportable (AR) – for minor changes that do not affect the safety, quality, or efficacy of a product.

Change Being Effected (CBE) – for minor changes that are required to be submitted to FDA at the time a change is made.

Change Being Effected in 30 days (CBE30) – changes must be submitted to FDA and following the receipt of their acknowledgement letter, are required wait 30 days before implementation.

Prior Approval Supplement (PAS) – are major changes that a company must submit to FDA and obtain approval before implementing. Comparability protocols are a subset of PAS.

How InViva can help with filing variations

InViva helps clients overcome the challenges and complications of filing licence variations for pharmaceutical, biopharmaceutical, healthcare, and OTC products globally. InViva’s extensive experience includes:

• Managing generics products

• Managing product life cycles

• Determination of the variation / amendment type and whether variations can be grouped

• Compilation and preparation of documents for submission to the FDA, EMA, or MHRA including replacement sections, forms, expert reports, letters etc.

• Publishing, submission, and management of the variation through the review and approval process including responding to Board of Health requests for Information (RFIs).

Audits are a critical pillar for the assurance of quality standards and should be designed to challenge pharmaceutical manufacturers and their related suppliers by asking “do you do what you say you do?”

Not surprisingly, regulatory agencies conduct detailed and robust audits in a variety of reasons including:

• Before a Marketing Authorisation is granted

• To identify any cGMP compliance issues or concerns and to ensure adequate remediation prior to granting a licence authorisation

• As a “for cause” audit to investigate concerns over the control, compliance, and conformance of a manufacturer.

Regulatory Agency Audits

Regulatory agency audits are often feared by pharmaceutical companies, but with appropriate, tailored preparation and management, audits can be conducted smoothly and be informative on a regulatory agency’s view of specific aspects of quality management.

Anticipating problems before they are highlighted by inspectors as well as ensuring corrective actions to address areas of weakness have been documented and ensuring corrective actions are in place can avoid potentially damaging regulatory action. All GMO manufacturers and licence holders are required to undertake periodic self-audits.

Self-audits ensure licence holders (MAA, GMP, GDP, etc) are prepared and audit ready. They are independently performed by qualified vendors in order to assess whether the appropriate systems and processes have been implemented and are being followed to provide satisfactory pharmaceutical, biopharmaceutical, healthcare and medical devices products.

These audits ensure that an organisation is following the legal and regulatory requirements as laid down by the FDA,  EMA, MHRA and other relevant competent authority.

Types of Audits​

There are many different types of audits. Some of the more frequent types include:

• System audits

These assess how a manufacturer operates using processes and systems. Each company has a range of systems designed for their specific business operations. These can be IT / IS systems including databases, Quality Systems, etc.

• Product / departmental audits

These assess the wide range of departments involved in the manufacture, testing and release of a product within a pharmaceutical company. Regular auditing ensures on-going compliance to company and regulatory systems and procedures.

Post-marketing surveillance for pharmacovigilance is performed to confirm that a product continues to be free from any unknown side-effects and complies with the regulations laid down by the FDA or EMA

• Quality / compliance audits (or self-audits)

These allow companies to perform internal audits or regulatory inspectors to perform formal audits on manufacturing facilities and operations to confirm compliance to cGMP. These audits assess all areas mandated by cGMP regulations including; quality systems (change control, OOS, deviations, training, etc. ), manufacturing processes, facilities, utilities, equipment, method validation, etc.

Self-audits can help manufacturers to continually improve and refine their quality systems and prepare for regulatory, GMP, or clinical audits, and for agency pre-approval inspections. Agency inspections form a critical part of product review and approval and include assessments such as pre-approval inspections.

• Conformance audits or product conformance

These are the on-going maintenance of the Marketing Authorisation (MA) and the avoidance of registration drift. A key element to the maintenance of the MA is the robust implementation of change control throughout the business to ensure appropriate controls are in place for on-going product conformation.

Registration drift occurs when there is a loss of synchronicity between an MA and the manufacturing, testing and release activities.

• Regulatory audits or regulatory self-audits

These audits demonstrate adequate levels of control over regulatory systems, such as MA visibility, MA change control, regulatory commitments tracking, license variations tracking, and other bespoke systems and procedures designed around the company’s business operations.

How InViva can help with audits

InViva holds and maintains its own GMP licence and provides on-going support to companies with a full range of tailored internal self-audits.

InViva always works to the latest legislations and regulations and our highly experienced regulatory affairs and quality assurance consultants have a strong track record of delivering pragmatic solutions to ensure problems are quickly identified and fixed.

InViva also provides assessment on the level of product conformance and registration drift through gap analysis, offering full license remediation services and tailored sustainable maintenance solutions to ensure ongoing conformance.