What is there in Revised ICH Q9 Part 1

1.High levels of subjectivity in risk assessments and in QRM outputs

Subjectivity is commonly present in a QRM process, as it can be introduced in the many risk assessments, especially in how hazards, harms and risks are perceived. With the revision of the ICH Q9, in a risk assessment, the terminology of the first step has been altered from “Risk Identification” to “Hazard Identification”, for improved alignment with the current definition of Risk Assessment in the guideline. 

The hazards must be identified and later proceed with the analysis and evaluation of risk, regarding the exposure. No further alterations in the risk assessment suggested flow were implemented. Nonetheless, subjectivity in a QRM process can never be fully eliminated – it may be restricted by acknowledging partiality, the application of proper QRM tools and a maximization of the use of relevant data and sources of knowledge.

2. Failing adequately management supply and product availability risk

Quality/manufacturing issues, including noncompliance with Good Manufacturing Practice (GMP), have been a frequent cause of product availability issues. Despite the guideline addressing this topic in its definition of harm as a form of “loss of product availability”, an effective pharmaceutical quality system should empower supply chain robustness and sustainable GMP compliance.

 QRM can help design monitoring systems for detection in departures from a state of control regarding product availability of the supplier, robustness of manufacturing facilities in the process, and acceptability of supply chain partners over the lifecycle. The new revision of Q9 addresses different factors that could affect reliability, such as the Manufacturing Process Variation and State of Control, Manufacturing Facilities and Oversight of Outsourced Activities and Suppliers.

Statistical Process Control in Pharmaceutical Quality Assurance

Statistical Process Control in Pharmaceutical Quality Assurance 

1.Control Charts: X-bar, R-chart, S-chart, and p-chart keep process variation in check.
2. Pareto Analysis: Pinpoint significant quality influencers for targeted improvements.
3. Histograms: Illuminate data distribution aiding in process stability assessments.
4. Scatter Diagrams: Visualize variable relationships to enhance quality mechanisms.
5. Cause-and-Effect Diagrams: Uncover quality issue roots with Fishbone Diagrams.
6. Process Capability Analysis: Evaluate if processes meet quality benchmarks.
7. Regression Analysis: Probe variable relationships crucial for quality optimization.
8. FMEA: Prevent quality issues by identifying potential failure modes.
9. ANOVA: Compare means across groups to ensure quality consistency.
10. Trend Analysis: Proactively manage quality by spotting data patterns.
11. Control Plan: Outline steps to uphold quality standards throughout production.

FDA Requirements for Process Validation

Synopsis of the US FDA 483on Process Validation 

In the Warning Letter, the FDA criticised the fact that no microbiological tests were named in the validation protocol and that the active ingredient specification did not correspond to the current process. Process validation studies were also missing for other medicinal products with regard to different active ingredients and dosage forms.

In the company's response letter, the FDA lacked a detailed description of how the company will ensure in future that the manufacturing process consistently produces medicinal products of suitable quality. The FDA refers to the validation life cycle and specifically mentions the importance of developing the manufacturing process and monitoring after the actual validation. Each significant stage of a manufacturing process must be adequately developed and ensure the quality of the starting materials used, the in-process materials and the finished drug product. Process qualification studies include intensive monitoring and testing of all significant process steps to characterise within-batch variation and evaluate batches to determine whether an initial control state has been achieved.

Successful process qualification studies are required prior to commercial distribution, according to the FDA. Referring to its process validation guidance, the FDA writes that without adequate process validation that considers all production factors and parameters that may affect product quality, the company lacks the basic assurance that it can reproducibly deliver products that meet specifications.

Specifically, the FDA requires:

A detailed summary of the validation programme to ensure that a "state of control" is maintained throughout the product life cycle, together with the associated procedures.

A description of the Process Performance Qualification (PPQ) programme

A description of the monitoring activities to assess intra-batch and inter-batch variability to ensure state of control

A schedule for the implementation of PPQ for each of the marketed medicinal products.

A detailed programme for the development, validation, maintenance, control and monitoring of each manufacturing process, with regard to intra- and inter-batch variability, with the aim of achieving a state of control

A programme for the qualification of facilities and equipment.

A comprehensive, independent assessment of the change management system. This assessment should include procedures to ensure that changes are justified, reviewed and approved by your quality unit. Your change management programme should also include requirements for determining the effectiveness of changes.

US FDA 483 2024 Alkem Laboratories

The authority has issued a new Form 483 following an inspection of Alkem Laboratories Limited, a drug manufacturer located in Baddi, Himachal Pradesh, India. The document was published on 09 April 2024 and goes back to an inspection from 19 to 27 March 2024.

The FDA observed several deficiencies during the inspection, particularly related to the quality system. The 17-pages report lists a total of 10 observations.

One significant observation (Observation 1) relates to the failure to thoroughly review unexplained discrepancies and failures of batches to meet specifications. Specifically, there was a failure in the preventive maintenance of a Perkin Elmer UV Spectrophotometer, resulting in its retirement without conducting an investigation or impact assessment on previously generated test results. Batches tested with this malfunctioning instrument were released into the US market, raising concerns about the accuracy and reliability of the test results.

The other observations include the following aspects:

No shipping studies of finished products shipped to US markets were performed.

Change Controls are not managed and closed within the specified timeframe.

The company failed to adequately perform and assess the GxP impact for computerized system/software.

Appropriate controls governing computer acquired data have not been established.

The firm failed to handle and store drug product containers at all times in a manner to prevent contamination.

Analytical results were not documented according to the SOP.

No annual visual examination of reserve samples was performed.

Understand ICH Q7 S11

What is expected in terms of impurities for APIs extracted from herbal or animal tissue origin [ICH Q7, 11.2]?

In cases where the API itself is the extract from an herbal or animal tissue preparation, all constituents of this extract (concomitant constituents) might be considered to be part of the API. Therefore, a production process-related impurity profile (except, for example, solvents used in the process), would generally not be expected. However, for all APIs derived from herbal or animal sources, tests and limits for possible contaminants originating from these sources (e.g., pesticides, mycotoxins, viruses, herbicides, elemental impurities and wrong species) should be established, based on a risk assessment. In cases where herbal or animal sources provide material that is further processed to yield a chemically-defined API, all constituents other than the API are considered impurities. In this situation, the API manufacturer would be expected to establish an impurity profile as well as an API release specification that would include impurity limits. In any case, it is the API manufacturer’s responsibility to establish batch release specifications for APIs to ensure that they are safe and of high quality, consistent with appropriate regulatory requirements, applicable compendial specifications and regional expectations [ICH Q7, 11.21;  ICH Q9; ICH Q11

In cases where an API test method is changed, which method should be used for stability studies already in progress?

The company should decide and justify the decision of which method to use. All test methods for stability studies [ICH Q1A] should be validated and demonstrated to be stability indicating prior to use [ICH Q7, 11.51]. Any changes to stability test methods should be documented. Applicability of the changes to the existing stability studies should be assessed and may require filing in accordance with regional requirements for post-approval changes [ICH Q7, 13.11]. 

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.