Sun Pharma's Dadra unit gets USFDA warning letter

Sun Pharma's Dadra unit had received an Official Action Indicated (OAI) status from the USFDA on April 11 this year. This was after the regulator had inspected the facility between December 4 to December 15, 2023.

Sun Pharma's Dadra unit is involved in the production of oral solid dosage forms and in the manufacturing of the generic Revlimid, which has been a key driver of sales for many pharma companies including Dr. Reddy's, in recent times.

Warning Letter to Indian Sterile Manufacturer due to egregious GMP Deficiencies 17.06.2024

The nine-day FDA inspection of an Indian pharmaceutical manufacturer had already taken place in October 2023. Due to the numerous and, as the FDA itself writes, egregious GMP violations and the inadequate response to the list of deficiencies by the manufacturer, a Warning Letter has now been issued. 

Insanitary conditions

The FDA classifies the medicinal products manufactured by the Indian pharmaceutical manufacturer as contaminated because they were manufactured, packaged or stored under insanitary conditions. The FDA inspectors found the manufacturing facilities to be in a state of disrepair, inadequately cleaned and maintained. Among the findings mentioned were residues next to the HEPA filters in the ISO 5 area, several barefoot employees in an ISO 8 area and employees bringing materials into the ISO 7 area without the required protective clothing and gloves. Sterile filling takes place in a RABS, which was visibly dirty.

And even if these deficiencies would be enough, the FDA lists further critical GMP deficiencies in its Warning Letter.

Inadequate, aseptic working methods

The FDA describes deficiencies that were observed during the manufacture of sterile medicinal products: Employees used a cloth to wipe down parts of the filling line and conveyor belt in the ISO 5 areas. In addition, employees blocked the protective air flow by leaning over open product. Employees did not wear goggles and had exposed skin during line set-up and aseptic operations. In addition, the FDA criticised the lack of monitoring of aseptic behaviour and the effectiveness of employee training.

Deficiencies in the media fill

During the inspection, it was noted that the aseptic operations simulated during the media fill were not sufficiently representative of commercial aseptic manufacturing operations. As routine production staff do not record manual interventions in the batch documentation, the media fill programme lacks representative data to determine the number and duration of interventions to be simulated during the media fill. In addition, during the inspection, numerous procedures were performed during routine manufacturing that were not simulated in the media fill.

Inadequate smoke studies

The FDA also criticised the smoke studies conducted to show the flow in the aseptic processing areas. Several instances of turbulent airflow were noted in critical areas of the filling line, even directly above the filling line. In addition, the smoke study videos did not include the manual filling operations that simulate actual production. Also, not all parts of the line were assembled as used in routine production.

Deficiencies in environmental monitoring and data falsification

The FDA criticised the fact that the required number of samples for environmental and personnel monitoring were not collected in accordance with the manufacturer's procedures. Instead, interviews with employees and the management of the microbiology laboratory revealed that it is common practice to fabricate results for samples that were never taken. In addition, results were altered that would otherwise not fulfil the defined specifications. During the inspection, numerous limit violations were also found in environmental and personnel monitoring samples.

Ineffective quality system

According to the FDA, the manufacturer does not have an effective quality system in accordance with GMP. In addition to the lack of effective management oversight of its manufacturing and laboratory operations, the FDA found that the quality department was unable to exercise appropriate authority or had inadequately implemented its responsibilities. Company management should promptly and comprehensively evaluate the company's global manufacturing operations to ensure that systems, processes and products are in compliance with FDA requirements.

Delay in the recall of medicinal products

Due to the serious GMP violations and the associated patient risk, the FDA had already advised the manufacturer in a conference call on 25 October 2023 to recall medicinal products from the inspected facility. On 27 October, the FDA published its own announcement. Despite numerous attempts by the FDA to obtain a decision on a recall, the Indian manufacturer did not initiate the necessary recall until 15 November 2023, i.e. approximately three weeks after the initial discussion.

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CHMP confirms Suspension of Marketing Authorizations with Studies of Synapse Labs

The re-examination by the Committee for Medicinal Products for Human Use (CHMP) confirms the suspension of marketing authorizations with bioequivalence studies of Synapse Labs Pvt. Ltd.

In July 2023, critical inspection findings at Synapse Labs Pvt. Ltd, a contract research organization (CRO) in India, led the EMA to initiate an Article 31 referral procedure to assess the impact on the benefits and risks of medicinal products authorized on the basis of studies conducted at the CRO. After reviewing all information for the over 400 medicinal products tested by Synapse Labs Pvt. on behalf of EU companies, the CHMP has recommended the suspension for numerous generic marketing authorizations. For some marketing authorizations, sufficient data are available to demonstrate bioequivalence. For all other medicinal products, no or insufficient data were available to demonstrate bioequivalence. National authorities can defer the suspension of medicinal products of critical importance for a maximum of two years and companies must submit the required bioequivalence data for these medicinal products within one year. Applicants and marketing authorization holders have requested the CHMP to re-examine its opinion. In March 2024, the CHMP confirmed and adopted its final opinion.

This confirmation concludes the re-examination for some of the medicinal products concerned. The opinion will now be forwarded to the European Commission, which will take a final decision that is legally binding in all EU Member States.

Checklist for Implementation of GDP Principles - Part 8: Self-Inspections

According to Chapter 8 (Self-Inspections) of the EU GDP Guidelines (Guidelines of 5 November 2013 on Good Distribution Practice of medicinal products for human use - 2013/C 343/01) "self-inspections should be conducted in order to monitor implementation and compliance with GDP principles and to propose necessary corrective measures."

The RP is responsible to ensure this program is maintained and thus is responsible for keeping up to date with changes in legislation and regulations impacting the business with regards to GDP. Other departments may support the RP by performing local audits and/or participating in the organisation’s self-inspection program.

Checklist: Implementation of GDP Principles at Wholesale Distributors

The following checklist provides a generic overview and could be used as a minimum requirement related to Chapter 8 of the 2013 guidelines:

• A self-inspection programme is implemented to cover all aspects of GDP and compliance within a defined time frame
• Self-inspections are conducted in an independent and detailed manner (by designated competent person(s) from the company and independent external experts)
• Subcontracted activities are a part of the self inspection programme
• Reports contain all observations
• A copy of the report is submitted to the organisation’s management and other relevant personnel
• Causes of irregularities and/or deficiencies are determined and the CAPA is documented and followed-up

EU adopts Supply Chain Law - Implications for pharmaceutical Companies

On 24th of May 2024, the EU member states adopted the European Supply Chain Law which requires companies of a certain size to monitor and prevent negative impacts on human rights and the environment from their supply chain activities.

The directive applies to companies with more than 1,000 employees and a turnover of more than 450 million euros.

Companies addressed by the directive are obliged to:

Establish a risk-based system to remediate and prevent human rights and environmental impacts throughout the life cycle of production, distribution, transport and storage of a product or the provision of a service.

Ensure that their entire supply chain (e.g. subsidiaries or business partners) meets these obligations.

Take appropriate measures to prevent and remedy abuses caused by their own activities or by other actors in the value chain. Companies can be prosecuted under civil law and must pay full compensation for the damage caused.

Implement a climate change transition plan in accordance with the Paris Agreement.

The directive will be introduced gradually (depending on the size of the company):

3 years after entry into force, the directive will apply to companies with more than 5,000 employees and a turnover of 1.5 billion euros

4 years after entry into force, the directive will apply to companies with more than 3,000 employees and a turnover of 900 million euros

5 years after entry into force, the directive will apply to companies with more than 1,000 employees and a turnover of 450 million euros

Once signed by the President of the European Parliament and the President of the European Council, the Directive will enter into force 20 days after its publication in the Official Journal of the European Union. Member states have two years to implement the regulation at national leve

What is the history of current good manufacturing practices

The history of Current Good Manufacturing Practices (cGMP) dates back to the early 20th century in the United States. The first major event was the passage of the 1906 Food and Drugs Act, which required dangerous ingredients to be declared on product labels and prohibited adulterated and misbranded drugs[4]. This act led to the creation of the Bureau of Chemistry, which later became the Food and Drug Administration (FDA)[4].

In the 1920s, the FDA began to regulate the pharmaceutical industry more closely. The 1937 Elixir Sulfanilamide tragedy, which killed over 100 people, further emphasized the need for stricter regulations. This led to the development of more detailed guidelines for pharmaceutical manufacturing, including the creation of the Food, Drug and Insecticide Administration (FDIA) in 1937[4].

The modern cGMP regulations were formalized in 1969 with the publication of Part 128 of the Code of Federal Regulations (CFR). These regulations were later recodified as Part 110 in 1977. The FDA continued to refine these regulations over the years, including revisions in 1986 and ongoing efforts to modernize them in the 21st century[3][4].

The main objectives of cGMP are to ensure the quality and safety of products by controlling manufacturing processes, maintaining clean and hygienic facilities, and implementing quality control measures. The regulations have evolved to address specific industry needs and technological advancements, with a focus on preventing harm to consumers and patients[1][2].

Automated Visual Inspection: False rejections

During the validation and operation of fully automated inspection machines (AVI), there are always problems with high false reject rates, i.e. the incorrect rejection of good objects. Are there GMP requirements in this regard?

As the automatic inspection systems are also able to recognise much smaller particles than humans, more or less large quantities of objects that were rated as good by an employee in the manual inspection [humans are still considered to be the gold standard in the 100% visual inspection] appear again and again in the eject of the AVI.

 In addition, a fully automated system could also have problems with air bubbles and reject objects with air bubbles as faulty. Ultimately, the trick is to configure the system in such a way that no objects with very small particles (invisible to humans) are rejected. There are companies in which objects rejected by the automatic system are checked again by manual inspection staff. However, this method harbours the risk that objects that actually have defects are suddenly judged to be free of defects by the employee. The FDA could also regard this procedure as unauthorised 'testing-into-compliance'.

Two conclusions can be drawn from the perspective of GMP. The rejection of objects without defects does not harbour any risk for patients and therefore appears to be practicable. On the other hand, qualification as such could also be criticised, as a system that makes systematic errors is not sufficiently qualified. In any case, acceptance criteria for false rejects should be defined. If these are exceeded, certain measures must be taken, such as an investigation into the cause and, if necessary and justifiable, an additional 100% inspection.

To summarise, it can be said that there is no requirement to set a limit value for false rejects. On the other hand, it is advisable to set a limit value for these false rejects as well, usually during qualification. This is because a missing limit value and, above all, a very high number of good objects in the false rejects can jeopardise the entire qualification during a GMP inspection.

Update of Appendix 1 for Nitrosamines

The nitrosamine Q&A document "Questions and answers for marketing authorization holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products" of the EMA/CMDh contains three appendices (Appendix 1-3) in its current version of January 2024. These documents are published on the EMA website and can be viewed under "Questions and answers".

Appendix 1 "Acceptable intakes established for N-nitrosamines" was prepared by the "Non-clincal Working Party (NcWP)" and the information provided there for the acceptable intakes (AIs) is based on the "Carcinogenic Potency Categorization Approach (CPCA)". In May 2024, new substances were added to Appendix 1, which consists of a tabular list of substances, and some existing entries in the list were updated. Sixteen substances were added and are marked in red and clearly recognizable in the list of acceptable intakes (AIs). These include:

2-(4-nitrosopiperazin-1-yl)ethanol

3-((ethyl(nitroso)amino)methyl) benzenesulfonate

4-nitroso-methyl piperazine-1-carboxylate

N-(2-hydroxy-2-phenylethyl)-N-(4-nitrophenethyl)nitrous amide

N-(4-aminophenethyl)-N-(2-hydroxy-2-phenylethyl)nitrous amide

N-nitroso-articaine

N-nitroso-desmethyl-edoxaban

N-nitroso-fenfluramine

N-nitroso-furosemide

N-nitroso-N-desmethyl-dextromethorphan

N-nitroso-posaconazole Impurity 1

Rivaroxaban Nitroso Impurity 1

Rivaroxaban Nitroso Impurity 2

Rivaroxaban Nitroso Impurity 5

N-nitroso-trientine Impurity 1

N-nitroso-vibegron

The entries for the substances "N-nitroso-folic acid" and "N-nitroso-lisinopril" have been updated.

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Equipment Qualification outline in light of regulatory

Regulatory requirements significantly influence the equipment qualification process in the pharmaceutical industry. The key regulatory bodies, such as the FDA and EMA, provide guidelines and regulations that outline the requirements for equipment qualification and process validation. These regulations ensure that equipment is properly installed, operated, and maintained to ensure the quality and safety of the final product.

The FDA's 21 CFR Title 211.63 emphasizes that equipment used in the manufacture, processing, packing, or holding of a drug product shall be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance[1][3]. Similarly, the EU's EudraLex – Volume 4 – Good Manufacturing Practice (GMP) provides detailed guidance on qualification under Annex 15: Qualification and Validation[1][2].

The FDA's Process Validation Guidance explicitly states that equipment qualification is an integral part of the process validation programme[3]. This means that equipment qualification is not just a standalone process but is closely tied to the overall process validation lifecycle, which includes process design, process qualification, and continued process verification[2].

The regulatory requirements also emphasize the importance of proper documentation and reporting. Manufacturers must maintain detailed protocols, reports, and standard operating procedures (SOPs) to document the qualification and validation activities. These documents serve as a comprehensive record of the qualification and validation processes, providing evidence of compliance with regulatory requirements[2][4].

In summary, regulatory requirements play a crucial role in shaping the equipment qualification process in the pharmaceutical industry. They ensure that equipment is properly installed, operated, and maintained to ensure the quality and safety of the final product, and that the process is thoroughly documented and validated[1][2][3][4].

Citations:

[1] IQ, OQ, PQ: Essential Steps for Equipment Qualification https://zamann-pharma.com/2024/04/22/iq-oq-pq-essential-steps-for-equipment-qualification/

[2] Introduction to Equipment Qualification and Process ... https://www.linkedin.com/pulse/introduction-equipment-qualification-process-industry

[3] What are the FDA Requirements for Equipment Qualifications? https://www.gmp-compliance.org/gmp-news/what-are-the-fda-requirements-for-equipment-qualifications

[4] What You Need To Know About Equipment Qualification https://boracdmo.com/what-you-need-to-know-about-equipment-qualification/

[5] Qualification of manufacturing equipment. | PPT - SlideShare https://www.slideshare.net/slideshow/qualification-of-manufacturing-equipment/248915750

Advancements and knowledge gaps in ICH Q2(R2)

Starting with the relationship between ICH Q14 and Q2(R2), the authors take a critical look at the new aspects incorporated in ICH Q2(R2). The concepts of selectivity and specificity, range and response, as well as accuracy and precision are discussed in more detail. The authors also identify areas needing additional guidance and compare how the latest ICH Q14/Q2(R2) guidelines align with US pharmacopeial approaches.

The authors conclude that "the revised ICH Q2(R2) guideline updates terminology and broadens the scope of techniques/products applicable, improving validation requirements for uni- and multivariate analytical procedures, while maintaining traditional approaches." It also says that "while both Q14 and Q2(R2) align with principles outlined in USP <1220>, further clarity and alignment between the two guidelines are needed to promote a comprehensive lifecycle approach."

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