USP plans new Chapter on Process Analytical Technology (PAT)

The United States Pharmacopeia (USP) is developing a new General Chapter dedicated to Process Analytical Technology (PAT), aiming to provide guidance on its definition, attributes, enablers, and practical applications in the pharmaceutical industry.

The chapter will focus on aligning with current scientific and regulatory standards, emphasizing real-time monitoring, control, and assurance of product quality throughout the manufacturing process. According to a General Chapter Prospectus published on 29 March 2024, "the scope extends to the use of PAT for process understanding and optimization, including applications in Continuous Process Verification (CPV) and Real-Time Release Testing (RTRT). The chapter will address the regulatory impact of PAT and its role in complying with quality standards."

The preliminary outline is as follows:

Introduction

Definition and Core Attributes of PAT

Key Enablers of PAT

Regulatory Considerations

Implementation Strategies

Applications of PAT

Emerging Trends and Technologies

USP invites early input from stakeholders on this proposed General Chapter, which is expected to be published for comment in the Pharmacopeial Forum. Comments on the proposed outline are due to the USP by 28 April 2024.

Do GMP inspectors no longer go to China?

Counter-Espionage Law

This law also known as counterintelligence, is a type of activity that protects an agency's intelligence program from another agency's. It involves detecting, destroying, neutralizing, exploiting, or preventing espionage activities. Counter-espionage can include: identification, penetration, manipulation, deception, and repressionp

China has revised its counter-espionage law. Compared to the previous version, the new version expands the government's powers to combat espionage and emphasises the role of the public in this task. In theory, activities carried out as part of an audit or inspection can now also be punishable by law. Espionage suspects may be prevented from leaving China by order of the national security authorities at provincial level or higher. This provision also applies to foreigners.

Now, following the German Medicines Manufacturers Association (Bundesverband der Arzneimittel-Hersteller, BAH), the Handelsblatt (a German business and financial newspaper) has also taken up the matter. The article "Antibiotics: Pharmaceutical inspectors no longer dare to visit China" ("Antibiotika: Pharma-Inspekteure trauen sich nicht mehr nach China"), Handelsblatt, 10 April 2024, reports on the potential impact of the stricter security laws in China on inspections and audits by German authorities and pharmaceutical companies. These laws, in particular the anti-espionage law, are quite vaguely worded, meaning that any information gathering could potentially be criminalised, causing uncertainty among foreign companies. In particular, this may affect inspection and audit activities in China. And inspections and audits that are not carried out could further exacerbate bottlenecks in the supply of medicines in the EU.

According to research by Handelsblatt, German GMP inspectors, who normally inspect production facilities on site in China and then issue GMP certificates, have already partially suspended their activities due to fears of problems.

The German Medicines Manufacturers Association (BAH) has appealed to Federal Chancellor Olaf Scholz to address the problem during his visit to China and find a solution. One possible solution could be a "Letter of Intent" in which the Chinese government clarifies that the data collected during GMP-inspections does not fall under the anti-espionage law.

Understand ICH Q7 S6

Is it expected that campaign manufacturing be addressed in cleaning validation? 

Yes. The cleaning validation section [ICH Q7, 12.7] does not specifically address campaign manufacture. However, sections [ICH Q7, 5.23, 8.50] set forth the expectations that equipment be cleaned at appropriate intervals (e.g., time or number of batches) to prevent build-up and carryover of contaminants so that they do not adversely alter the quality of the API. The appropriate interval is confirmed during cleaning validation. 

At product changeover, are both visual examination and analytical testing necessary to verify that equipment is clean? 

Appropriate cleaning validation verifies that the cleaning process is effective. During cleaning validation, both visual examination and analytical testing should be used to verify cleaning effectiveness [ICH Q7, 12.72-75]. Once the cleaning process is validated, routine monitoring of cleanliness of equipment at product changeover should include visual inspection [ICH Q7, 12.76]. Frequency of analytical testing to verify ongoing effectiveness of the validated cleaning process is determined by the API manufacturer using a risk-based approach. In situations where the cleaning process is not yet validated, both visual examination and analytical testing are expected. For APIs with a retest date, [ICH Q7, 6.13] states that records related to production, control and distribution should be retained for at least 3 years after the API batch is ‘completely distributed’, which is understood as the complete distribution of the entire batch of the API by the API manufacturer to the next party in the supply chain. In the case of APIs handled by agents, brokers, traders, distributors, repackers, and relabellers [ICH Q7, 17], ‘completely distributed’ refers to distribution of the received quantity of the batch of API. The intent of ICH Q7 is to retain records for the period of time that the API could be on the market in order to investigate any problems and/or product complaints. Based on accepted industry practice at the time ICH Q7 was written, it was not anticipated that a manufacturer would set a retest date longer than 3 years. However, the use of ‘at least three years’ in this section of ICH Q7 covers longer record retention periods, which is in alignment with the basic GMP principle and/or regional requirements that records be retained for the entire period the material is available on the market. It is good industry practice to consider retaining records for the period of time the drug product(s) in which the API was used may be available on the market. 

Understand ICH Q7 S5

To what extent can quality risk management be used in establishing appropriate containment measures to prevent cross-contamination? 

The principles of quality risk management [ICH Q9, Annex II.4] should be applied to the design of buildings, facilities and controls for the purpose of containment, taking into consideration the pharmacological/toxicological/chemical/biological properties of the raw material, intermediate and/or API to be handled or manufactured. Appropriate containment measures and controls [ICH Q7, 4.42] include but are not limited to the following: • Technical controls (e.g., dedicated production areas, closed/dedicated HVAC system, closed manufacturing systems, use of disposable technologies, design of facility and equipment for containment and ease of cleaning) 

Procedural (organisational) controls (e.g., cleaning, personnel flow, environmental monitoring and training) Monitoring systems are important to check the effectiveness of the containment controls. 

For dedicated equipment, is ‘visually clean’ acceptable for verification of cleaning effectiveness, (i.e., no expectation for specific analytical determination)?

Visually clean’ may be acceptable for dedicated equipment based on the ability to visually inspect and sufficient supporting data from cleaning studies (e.g., analytical determination to demonstrate cleaning effectiveness) [ICH Q7, 12.76]. Equipment should be cleaned at appropriate intervals (e.g., time or number of batches) to prevent buildup and carryover of contaminants (e.g., degradants or objectionable levels of microorganisms) so that they do not adversely alter the quality of the API [ICH Q7, 5.23, 12.7].

Should acceptance criteria for residues be defined for dedicated equipment? 

Yes. Regardless of whether equipment is dedicated or not, it is expected that acceptance criteria for residues be defined and that the equipment be cleaned at appropriate intervals to prevent build-up and carry-over of contaminants. Intervals can be based on number of batches, product change-over, time, etc. [ICH Q7, 5.22, 5.23, 5.24, 5.25, 8.50]. Cleaning intervals and acceptance criteria should be established based on an understanding of the process/reactions/degradation, taking into account solubility, potency, toxicity, etc. Establishment of acceptance criteria does not necessarily imply sampling and testing after every cleaning. Visual inspection of equipment for cleanliness is an expectation of [ICH Q7, 5.21]. Where validation data has confirmed effective cleaning, cleaning procedures should be monitored at appropriate intervals [ICH Q7, 12.76]. 

Understand ICH Q7 S4

What is the intent of the statement in [ICH Q7, 3.12] ‘training should be periodically assessed’? 

In [ICH Q7, 3.12], the statement ‘training should be periodically assessed’ refers to a system to evaluate if personnel remain proficient and competent in their job tasks and responsibilities, and whether more frequent, additional, or new training is needed and recurring training is up to date. 

Does ICH Q7 expect the use of a consultant and can a company delegate tasks and/or responsibility to a consultant?

ICH Q7 does not expect the use of a consultant. Consultants may perform delegated tasks and/or provide advice. However, the ultimate responsibility for API quality must not be delegated [ICH Q10 2.7, ICH Q7 2.2, 3.3]. 

When are dedicated production areas expected? 

ICH Q7 expects dedicated production areas for highly sensitizing materials such as penicillins and cephalosporins because of the patient risk (e.g., anaphylactic shock to penicillin-allergic patients) from trace amounts of these compounds in other medicines [ICH Q7, 4.40]. For materials of an infectious nature or high pharmacological activity or toxicity, a risk-based approach should be used to determine appropriate containment measures, which may include validated inactivation, cleaning and/or dedicated production areas [ICH Q7, 4.41]. While ICH Q7 does not define high pharmacological activity

or toxicity, these are generally determined by evaluating relevant animal and human data collected during research and development. Important considerations in this evaluation of pharmacological activity or toxicity may include Occupational Exposure Limit (OEL), Permitted Daily Exposure (PDE), Acceptable Daily Exposure (ADE), Threshold for Toxicological Concerns (TTC), No Observed Adverse Effect Level (NOAEL) [ICH S-guidelines, ICH E2E, 2.1.1], and the consequences of cross-contamination [ICH Q9, 4.3]. 

Quality Metrics US FDA

FDA's current approach to overseeing pharmaceutical manufacturing emphasises the importance of quality metrics in ensuring product safety and efficacy. These metrics, which are an integral part of the FDA's inspection and compliance strategies, aim to promote continuous improvement and innovation within the industry. While the FDA focuses primarily on Quality Metrics, the concept of Key Performance Indicators (KPIs) also plays a critical role as it provides a broader perspective on operational efficiency and strategic management.

The effective use of metrics is essential for robust quality management at a site. They also play a crucial role in selecting suppliers, monitoring contract activities and minimising supply chain disruptions. The FDA itself uses metrics to develop compliance and inspection guidelines, improve the prediction and mitigation of drug shortages, and optimise risk-based inspection planning.

The FDA is also working on a Quality Metrics Reporting Programme to support its quality monitoring activities, with the goal of obtaining more quantitative and objective measures of manufacturing quality and reliability. In addition, the FDA's Center for Drug Evaluation and Research (CDER) is implementing a programme to promote Quality Management Maturity (QMM) in drug manufacturing facilities. The QMM programme promotes the adoption of quality management practices that go beyond CGMP requirements and aims to foster a strong quality culture, recognise advanced quality management practices, identify areas for improvement and minimise risks to product availability.

Key Performance Indicators (KPIs) are important metrics used in pharmaceutical manufacturing to measure and evaluate the effectiveness of operations and processes against defined goals. While the FDA emphasises quality metrics to monitor the product and process lifecycle in pharmaceutical manufacturing, KPIs can complement these by providing insights into compliance and operational efficiency.

Supplier or Vendor Qualification

Supplier Qualification Overview 

The "Best practices guide for managing suppliers of API manufacturers" was finalised by the "APIC Supplier Management Task Force" in March 2024 and is now available on the APIC website. It emerged from the document "Supplier Qualification and Management Guideline", which was first published in 2009, and now replaces it in its entirety. The previous document has been completely revised, although the original annexes have been retained and an additional Annex 2 entitled "Commitment declaration (template)" has been added.

The new guide contains the following chapters and sub-chapters:

1. General Section
    1.1 Introduction 
    1.2 Objectives
    1.3 Scope
    1.4 Overall Process for Supplier Management

2. Supplier Management
    2.1 Selection Phase
    2.2 Qualification Phase
    2.3 Operational Phase
    2.4 Termination Phase

3. Risk Management applied to Supplier Management
    3.1 Risk management process
    3.2 Risk Identification and Analysis
    3.3 Risk Evaluation and Risk Review
    3.4 Risk control

4. Auditing
    4.1 General
    4.2 Audit organisation
    4.3 Audit Types
    4.4 Audit rating
    4.5 Refusal of audits

5. Quality agreements
    5.1 General
    5.2 Refusal or partial acceptance of agreements

6. Definitions and abbreviations
7. References
8. Annexes
9. Version History

US FDA Warning Letter 09.04.2024

Your firm failed to have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release (21 CFR 211.165(a)).

Your firm manufactures over-the-counter (OTC) (b)(4) drug products, such as, (b)(4). Your firm failed to adequately test your (b)(4) drug product for identity and strength of active ingredients prior to release and distribution.

In your response, you state that you will perform an assay test of your (b)(4) for (b)(4) with a validated analytical method. Your response is inadequate. You failed to provide sufficient details such as your testing procedures or a risk assessment of products released without appropriate assay testing.

Because you lacked adequate testing of each batch of your drug product, you do not know whether they conform to all appropriate finished product specifications and are suitable for release and distribution.

2. Your firm’s quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22).

Your quality unit (QU) did not provide adequate oversight for the manufacture of your drug products. For example, your QU failed to ensure the following:

Appropriate production and process controls, including an adequate process validation program designed to assure drug products manufactured have the identity, strength, quality, and purity purported or represented to possess (21 CFR 211.100(a)).

Scientifically sound and appropriate test methods and standards used for testing your drug products (21 CFR 211.160(b)).

Complete data derived from standard preparation, sample preparation, and assay testing of your drug products was properly documented and retained (21 CFR 211.194(a)).

Adequate investigations and deviations (21 CFR 211.192).

Adequate cleaning and maintenance procedures, including an appropriate cleaning validation program for your non-dedicated manufacturing

Natco Pharma Ltd received a Warning Letter

Natco Pharma Ltd, a leading Indian pharmaceutical company, announced today that it has received a Warning Letter from the United States Food and Drug Administration (USFDA) regarding its manufacturing facility located in Kothur, Telangana.

The letter, dated April 8, 2024, follows a routine current Good Manufacturing Practices (cGMP) inspection conducted by the USFDA at the facility in October 2023.

The Kothur facility produces various pharmaceutical products for the company. While the company did not disclose specific details about the products manufactured at this site, it stated that the warning letter is not expected to disrupt supplies or impact existing revenues from the facility.

However, the letter may result in delays or withholding of pending product approvals from the Kothur site, it added.Hit Follow

Insufficient CAPA turned into Non-compliance

CAPA is a promise from the manufacturer that provide assurance to regulatory over a documentation. Failing to meet such promise will turn into a non compliance report by regulatory authority here is the example.

A follow-up GMP inspection was carried out at Cubit Lifesciences in India by the Malta Medicines Authority (MMA), an EU Competent Authority, early 2024. This inspection was in line with the recommendations from a previous inspection conducted about one year earlier, which had identified "2 critical, 3 major and a total of 17 other observed issues."

The main goal of the recent follow-up inspection was to "assess and validate the effective incorporation, spanning the entirety of the facility and the pharmaceutical quality system, of the documented Corrective and Preventive Actions (CAPAs) and commitments presented by Cubit Lifesciences in response to the February 2023 inspection."

However, the follow-up inspection revealed that some issues identified in the initial inspection were "not fully addressed and implemented," leading to the finding of "two critical, four major and twelve other findings." This indicated a lack of proper implementation of the necessary CAPAs.

As a consequence, the Inspection Review Group (IRG) at the Malta Medicines Authority has decided to issue a "Statement of Non-Compliance with the principles and guidelines of Good Manufacturing Practice laid down in Directive 2003/94/EC" for the site, reflecting ongoing concerns about compliance and quality management at Cubit Lifesciences.

Also for inspection observations, the causes of the problems identified would need to be thoroughly investigated and corrective and preventive actions (CAPA) should be defined to prevent recurrence. The implementation of CAPA following a root cause analysis (RCA) is crucial as it ensures that the identified causes are addressed through appropriate actions. The report emphasises the need for an in-depth root cause analysis and the implementation of effective CAPA.