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Our Blog

An ongoing series of informational entries

Emerging FDA Drug Inspection Trends in 2016

January 31, 2017

FDA Inspection Observation Trends for Drugs in 2016: Top Issues and how to prevent them Regulatory observations (483) over past years has forced Quality Executives to be on their toes. The top 5 key issues for 2016 are related to inadequate procedures and investigations, laboratory controls and aseptic processing. 1. Procedures not in writing and fully followed. 2. Lack of Scientifically sound laboratory controls. 3. Through investigation of discrepancies and failures. 4. The absence of written procedures. 5. Environmental monitoring system. How can these be prevented? Establishing a culture of quality is critical to prevent some of these issues. "We don't start any task until SOP is effective and we always follow our procedures" should be the mindset. A robust training program on conducting investigations and aseptic processing as a new employee orientation is a must to ensure product quality and patient safety. Laboratory controls issues can be prevented with robust method development in R&D. Most of the time, all the required data is not collected during method development to support the investigations conducted during manufacturing, resulting in inadequate justifications. This should be followed by training, routine internal audits, and standardization in quality laboratories, such as creating a guideline or standards for method validation, stability etc.

Mutual Recognition of Inspections between EU and US Authorities

January 22, 2018

European Union (EU) Authorities and Food and Drug Administration (FDA) signed the mutual recognition agreement (MRA) in February 2017, which enters into force on 01 November 2017. The agreement is an annex to the EU-US MRA, which was signed in 1998 but is not yet implemented.

This MRA will allow EU and US regulators to rely on each others GMP inspections and share inspection outcomes. Additionally, after the transition phase, it will waive any requirements for importation batch release testing of products on entry into their territories. The aim of this MRA is to make better use of inspection capacity and reduce duplication.

Recent Updates: In June 2017, the European Commission confirmed that the US FDA has the capability, capacity and procedures in place to carry out GMP inspections at a level equivalent to the EU. In October 2017, the FDA confirmed the capability of eight EU Member States (Austria, Croatia, France, Italy, Malta, Spain, Sweden, and the  United Kingdom).

Imported products still need to be batch tested until the FDA recognizes all EU Member States' authorities for human pharmaceuticals.

Products Covered are human chemical pharmaceuticals, medicinal gases, human biologicals, including immunological and biotherapeutics, human radiopharmaceuticals, homeopathic medicines if classified as medicinal products, vitamins, minerals and herbal medicines if classified as medicinal products, active pharmaceutical ingredients and intermediate products and bulk pharmaceuticals.

Products Excluded are Human blood and Plasma, Human tissue and organs, Veterinary immunological and Advanced Therapy Medicinal Products.

Brexit and Pharma Industry

February 6, 2018

The United Kingdom (UK) decided to withdraw from the European Union on 23 June 2016. The two-year process of leaving the EU on 29 March 2019 was triggered on 29 March 2017.

Medicines and Healthcare Products Regulatory Agency (MHRA) issued an updated briefing to pharmaceutical companies in January 2018 indicating that current regulatory relationship remains unaffected. The UK continues to be full member state till March 2019 and will fulfill its responsibilities as a member state until then. MHRA will continue to work closely with EMA in planning for the UK’s withdrawal and will ensure minimum burden and sufficient implementation time for companies. 

On the other hand, EMA has mapped out the process for handling the Brexit related changes to alleviate some of the regulatory uncertainty for Pharma companies. On 24 November 2017, EMA issued guidance for procedures related to Brexit for medicinal products of human and veterinary use. This guidance indicates that as of 30 March 2019, the UK will become the third country. Market Authorization Holders (MAH) and applicant currently established in the UK need to ensure that necessary changes are made by 30 March 2019. This means that MAH established in the UK will have to transfer from the current UK-based MAH to a different legal entity established in the EEA. This imposes a significant burden on EMA and pharma companies to complete and fully implement all transfers by 30 March 2019.

Data Integrity

February 7, 2018

Regulators around the globe have issued guidance’s on data integrity in the last five years. This is not something new. It has been there since drug development started. However, it has surfaced as a key issue in the last five years during regulatory inspections of raw materials and drug suppliers overseas.

In simple terms, data (paper or electronic) should be complete, consistent and accurate throughout the data life cycle, i.e. from raw data generation and recording through use, migration, retention, archival and destruction. It is critical to ensure data integrity because data errors could make an adulterated drug batch to reach patient, thus impacting patient safety.

What is the solution? The path forward includes 2 main steps: (A) Conduct a thorough assessment of current data integrity systems and identify if there are existing issues. Remediate the existing issues. (B) Develop and implement robust and sustainable data integrity systems. Train employees and establish the governance structure to provide oversight for management and continuous improvement of data integrity.

Quality and Regulatory Intelligence

October 26, 2018

"An organization's ability to learn, and translate that learning into action rapidly, is the ultimate competitive advantage" Jack Welch

There are 4 key attributes of successful compliant companies. 1. Rigorous internal audit program 2. Effective CAPA 3. Robust quality and regulatory intelligence system that provides the knowledge needed to stay appraised of a dynamic regulatory environment 4. Commitment to act upon intelligence in a timely manner.

What is regulatory and quality intelligence? Regulatory information (oral or published) is the raw data used to create regulatory intelligence. Regulatory information can be internal (observations from internal and external audits) or external (guidance, regulations or regulatory trends). The data analysis, using data to create innovative strategies and integration into company corporate policies and procedures produces regulatory intelligence.

Defining an effective regulatory intelligence system is critical. An effective regulatory intelligence system recognizes, tracks and ultimately predicted trends. There are 3 main steps in any regulatory intelligence system, which are information gathering, information mining and transforming knowledge into actions.

Regulatory intelligence helps timely and efficient product approval and maintenance. A good regulatory intelligence system ensures the continuous updates and improvement of existing quality systems based on evolving regulations and regulatory landscapes.

Change Managment

Brexit on Horizon

October 26, 2018

We have been hearing about Brexit for quite some time. Brexit is impacting the life science industry in the UK and EU in several ways but mainly by causing regulatory uncertainty and patient access to medicine or supply chain impact.

EMA issued guidance on 24 November 2017, for market authorization holders to transfer current UK based market authorizations (MA) to a different legal entity in EEA, which needs to be completed by March 2019.

The MHRA position will be clear after further negotiations but there is a risk of Brexit disrupting the supply chain due to complexities caused by additional importation testing, batch certification and regulatory inspections. It has to be seen how negotiations will end but pharma companies need to be ready with Brexit strategies for supply chain management such as adding additional capacity for MA transfer, batch certifications and additional storage capacity to hold stock during the Brexit transition period.

Change Management

October 26, 2018

Change Management is a critical quality system during the drug development and commercial phase of a pharmaceutical product. Post-approval changes are first categorized as minor, moderate and major based on product quality, product efficacy and patient safety risk. The second is a risk-based categorization of regulatory communication as prior approval supplement (PAS) or notification. Any changes to established conditions (EC) in common technical document (CTD) necessitates submission to regulatory authority as PAS or notification.

An effective change management system requires processes for science-based risk assessment and categorization of the proposed change, approval by all impacted stakeholders, implementation as per approved protocol and post-implementation verification for unintended consequences, including the risk management if the change is not implemented.

Several regulatory guidance’s including recently published ICH Q12 Draft guidance provides a risk-based approach for implementation of post-approval CMC changes.

Out of Specification (OOS) Results and Trending Program

October 26, 2018

MHRA guidance for handling OOS results was recently updated and is available on the MHRA website. FDA guidance for handling of OOS was initially issued in 1998 as a draft and was finally issued in 2006. MHRA guidance on handling OOS results was initially published in 2013 and was updated to add handling of microbiological OOS. MHRA guidance is complementary to FDA guidance and provides flowcharts for OOS investigations.

There are 3 phases of an OOS investigation. During Phase 1 and 2, an investigation is performed to determine the root cause of OOS in lab and manufacturing, respectively. During phase 3, a holistic assessment is performed to determine the impact of OOS result on the impacted & other batches, stability etc. and to implement appropriate CAPA.

There are two most common regulatory observations related to OOS. (1) An inadequate justification for invalidating tests and reoccurrence of invalid tests. (2) Inadequate and inconclusive investigation with no root cause and corrective actions.

Invalid tests should be trended based on root cause to enhance assay robustness, procedures or training program, implement CAPA and to prevent reoccurrence of invalid tests. The potential or most probable root causes should be determined, where root cause cannot be determined and appropriate CAPA should be implemented for process improvements, as applicable. However, if there are numerous OOS for the same test where the root cause cannot be determined, the question arises if the specifications are adequate for the test. Is there a need to improve the process or the assay or the specification? Also, if there are numerous OOS for the different tests where root cause cannot be determined, then OOS investigation procedure and training on root cause investigation needs to be enhanced.

Therefore, a good trending program for invalid tests and OOS test is very important to implement an effective CAPA and remediate OOS issues.

China issue the rule of accepting overseas clinical trial data of drugs

October 26, 2018

The China National Drug Administration issued the Guiding Technical Principles for the Acceptance of Overseas Clinical Trial Data of Drugs (“Principles”) on 10 July 2018, which standardize the rule of accepting the overseas clinical trial data of drugs.

According to the Principles, overseas clinical trial data provided by applicants for drug registration in China shall be complete, correct, true and traceable. The process of obtaining the overseas clinical trial data shall comply with both the Good Clinical Practice of China and the ICH. The applicant shall submit comprehensive data concerning biopharmaceutics, clinical pharmacology, effectiveness and safety. After a review, the CNDA may choose to fully accept, partially accept or refuse to accept the submitted overseas data.

Multi-national pharmaceutical companies will significantly benefit from these Principles, from the reduced cost of conducting clinical trials in China and the significantly reduced registration timeline.

5 Benefits of Quality Strategic Planning

February 21, 2020

Quality strategic plans strategies for risk mitigation, compliance improvement or new products/facility. There are always too many initiatives to complete in any organization. Strategic planning provides a structured approach to prioritize initiatives and goals based on risk. There are several tangible and intangible benefits of strategic planning. Tangible as well as intangible benefits create a high value in any organization. Following are 5 key benefits:

Benefit # 1: Risk Forecasting

The risk management process increases risk knowledge, reduces uncertainty and increases the ability to control/reduce risks. Strategic planning provides forecasting about how risks will be managed. 

Benefit #2: Decision making and complexity reduction

Strategic planning results in faster, more accurate and transparent decision-making processes and improved judgment. It also improves the ability to budget compliance goals proactively. Strategic planning provides clarity and reduces complexity for the implementation due to the prioritization of goals and initiatives. 

Benefit # 3: Quality Cost reduction

One of the tangible benefits is cost reduction as a result of planning for compliance and metric improvement. Improved cycle times, fewer nonconformances and less rejected material result in reduced cost of quality.

Benefit # 4: Effective QMR process

Strategic planning provides clarity on goals and their priority. Clearly prioritized goals make the quality management review process highly transparent and effective. It also improves management oversight, shared ownership of risks and visual performance dashboard.

Benefit # 5: Staff morale

Quality strategic planning improves employee morale and turnover due to transparency and clarity of goals, increased accountability and enhanced culture of quality.