Understand ICH Q7 S10

What is meant by ‘appropriate specifications (of each batch) prior to blending’ [ICH Q7, 8.41]? 

As a principle, no batches with Out of Specification (OOS) results should be blended [ICH Q7, 8.41]. Blending is defined in [ICH Q7, 8.40]. Individual intermediate and/or API batches should demonstrate conformance with the filed specifications prior to blending. In regions or circumstances where there are intermediates and/or APIs that do not require filing, conformance with the release specification should be demonstrated. 

What is meant by ‘APIs and intermediates can be transferred under quarantine to another unit under the company’s control when...’ and is this applicable to contract manufacturers?

ICH Q7, 10.20] states ‘APIs and intermediates should only be released for distribution to third parties after they have been released by the quality unit(s). APIs and intermediates can be transferred under quarantine to another unit under the company’s control when authorized by the quality unit(s) and if appropriate controls and documentation are in place’. The second sentence in [ICH Q7, 10.20] describes transport situations that are not considered distribution. It provides for physical movement (transfer but not release) of quarantined material to another unit. This unit can be on the same site, different site (within the same company), or a contract manufacturer (see final paragraph below). The goal of transfer under quarantine is to allow transportation and testing in parallel. Material that is transferred under quarantine is not to be used for further processing until all testing and quality review is complete and the material is released by the quality unit as defined in [ICH Q7, 2.22]. This provision for transfer under quarantine is included in ICH Q7 for situations where a company is shipping APIs or intermediates from one unit to another and has both the need to expedite the shipping and the material management system in place to prevent use of the material before full release. Examples of circumstances where transfer under quarantine may be needed include extraordinary supply chain requirement(s) (e.g., short shelf-life), and materials with a lengthy timeframe for required test(s) (e.g., some microbiological tests, etc.). With appropriate oversight as described in [ICH Q10 2.7], including a written agreement as described in [ICH Q7, 16.12], and appropriate ongoing controls, a contract manufacturer may be considered a ‘unit under the company’s control’. There is a joint responsibility by both parties to clearly justify and document the need to transfer the unreleased intermediate or API, and to ensure appropriate control is maintained to prevent use before full 

Understand ICH Q7 S9

Which tests are considered to be identity tests? 

For incoming production materials, identity tests and related methods should be used as described in the relevant sections of a Pharmacopoeia monograph, in an approved regulatory filing or in an in-house specification (including method/analytical procedure) [ICH Q7, 7.30]. When available, a discriminating test should be considered for identification testing. The visual examination of a label or the material is not considered sufficient except in the cases described in [ICH Q7, 7.32]. 

Is it possible to extend the expiry date or retest date of a raw material and what is the acceptable practice to determine how

Manufacturing and labelling of raw materials for use by API manufacturers is outside the scope of ICH Q7. As such, retest and expiry dates, as defined in ICH Q7, do not strictly apply to raw materials and may be used in a different manner by the raw material supplier. Expiry date, as defined in the glossary of [ICH Q7, 20], applies specifically to the API. API manufacturers may re-evaluate [ICH Q7, 7.5] and then use a raw material after the ‘expiry date’ or ‘retest date’, based on an appropriate scientific and risk-based justification (e.g., understanding of material attributes, testing, and stability). Similar justifications may be used to extend the date by which the material should be reevaluated. It is the responsibility of the API manufacturer to ensure the raw materials are appropriate for the intended use at the time of use. 

Can yield ranges defined for the first batch differ from latter batches within a campaign? 

Yes. Differing yield ranges [ICH Q7, 8.14] may be described and justified in the manufacturing procedure/master batch record explaining the ranges [ICH Q7, 6.41]. For example, the first batch in the series of production of batches of the same material (campaign) may leave residual material in the equipment, resulting in a low yield in the first batch and contributing to an increased yield in a subsequent batch of the campaign. 

Understand ICH Q7 S8

What is expected in terms of evaluation of suppliers of materials? 

Different phrases are used to describe the expectation for evaluation of suppliers of materials [ICH Q7, 7.11, 7.12, 7.31], including traders, if any. [ICH Q7, 7.12] states that all materials are purchased against a specification and from suppliers approved by the quality unit [ICH Q7, 7.31]. Prior to approval of any supplier, an evaluation should be conducted using a riskbased approach [ICH Q9, Appendix II.5; ICH Q7, 7.31].  More extensive evaluation is needed for suppliers of those materials classified as ‘critical’ [ICH Q7, 7.11].

What is meant by ‘full analysis’ [ICH Q7, 7.31] on batches of raw materials to qualify a supplier? 

A ‘full analysis’ should include all tests specified by the user of the raw material in the regulatory filing. In cases where no filing is required, the full analysis should include tests in other formal written specifications issued by the user of the raw material [ICH Q7, 7.31]. A raw material supplier’s Certificate of Analysis (CoA) may not necessarily align with the user’s specifications. 

Are on-site audits required in the evaluation of suppliers? 

No. An on-site audit is not required; however, an on-site audit could be a useful tool in the evaluation of a supplier. A risk assessment of the material or the service provided can be used to develop an audit strategy and manage the ongoing evaluation of suppliers [ICH Q7, 7.11, 7.31]. 

Understand ICH Q7 S7

What is meant by ‘completely distributed’ in [ICH Q7, 6.13], which states that ‘records should be retained for at least 3 years For APIs with a retest date, [ICH Q7, 6.13] states that after the batch is completely distributed’? 

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. 

Does a batch numbering system need to be sequential? 

No, [ICH Q7, 6.51] says only that batch production records should have a unique batch or ID number. ds? [ICH Q7, 2.3] does not specify who is responsible for the issuance of batch production records [ICH Q7, 6.5] as long as the issuance process is described in writing and approved by the quality unit [ICH Q7, 2.21]. 

Does the phrase ‘grouping of containers’ have the same meaning in [ICH Q7, 7.20 and 7.24]? 

The phrase ‘grouping of containers’ should be read in the context of each sentence. A grouping of containers refers to multiple containers physically secured by the supplier (e.g., shrink-wrapped pallet, etc.) usually intended for ease of shipment and reconciliation. [ICH Q7 7.20] is referring to incoming visual examination of materials before acceptance into the facility under quarantine. The phrase in [ICH Q7, 7.24], ‘grouping of containers (batches)’ contains an additional word ‘batches’ because this section is addressing the need to establish batch traceability for the incoming material. 

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.