White paper: Pharmaceutical Reduced Testing for the 21st Century – Risk-based approach for Skip lot or Periodic Testing of Starting Materials in Pharmaceuticals

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White paper: Pharmaceutical Reduced Testing for the 21st Century – Risk based approach for Skip lot or Periodic Testing of Starting Materials in Pharmaceuticals

Reduced Testing

Introduction

Pharmaceutical formulations are manufactured using starting materials, Active Pharmaceutical Ingredient, and Excipient. Since the pharmaceutical formulations directly impact the patients’ lives, manufacturers and marketing authorization holders are directly responsible to ensure their products’ quality, safety, and efficacy. In this article, we will discuss about reduced testing of active pharmaceutical ingredients, and other starting materials.

One of the essential elements to ensure the product quality is the quality of starting material. Quality of starting material can be ensured mainly in three ways;

(i) robust process of starting material manufacturer qualification,

(ii) robust supply chain, and

(iii) testing of starting materials.

Even though meeting the regulatory requirements is mandatory, other aspects are also important such as efforts are being made to test the material, inventory holds up till material gets a release, storage facility, products’ turnaround time (TAT), documentation, and quality events because false-negative results generated during the testing. Therefore, when reduced sampling, and periodic or skip lot testing are considered with scientific sound and risk-based approach within the scope of regulatory guidance, it fulfills both the aspects; quality assurance and economic aspects.

This white paper aims to give an overview of the viewpoints from different regulatory guidelines, pharmacopeias, and regulations on reduced sampling and testing. Identified regulatory guidelines complement the approaches for reduced testing and sampling illustrated in this article. These strategies will help to reduce the workload of releasing the incoming materials, which includes sampling, testing, and release.

This article covers the following key components:

  • Consideration of sampling approach;
  • The risk-based approach of vendor qualification;
  • Regulatory guidelines referring the minimum requirement of sampling, testing, and periodic or skip lot testing;
  • A practical approach for implementation of reduced sampling and testing;
  • Statistical evaluation of data to support reduced testing.

The white paper provides general guidance and a practical approach to implement reduced testing with the help of the quality risk management principle.

In this white paper, author tried to cover reduced testing FDA guidance, ICH guidelines for reduced testing, EMA guideline, and other guideline for reduced sampling and testing. These reduced testing guidelines will provide valuable insight about various approaches that cab be used to implement reduced testing.

Reduced Sampling Approach

According to the EudraLex Volume 4 – Good Manufacturing Practice (GMP) guideline, Annex 8: Sampling of Starting and Packaging Materials, “The identity of a complete batch of starting materials can normally only be ensured if individual samples are taken from all the containers and an identity test performed on each sample. It is permissible to sample only a proportion of the containers where a validated procedure has been established to ensure that no single container of starting material has been incorrectly labelled”.

In an ideal condition, Annex 8 suggests performing an identity test from all the containers, which means that one has to sample each container to perform identification testing.

However, in the second part of the paragraph, Annex 8 is permitting to differ that requirement with the condition that, if it can be assured by a validated procedure that no container is labeled incorrectly, it is permitted to sample only a proportion of the containers.

With further explanation, according to Annex 8, the following parameters can be considered for above-said validation.

  • Incoming raw materials manufacturer’s understanding of the GMP requirements of the Pharmaceutical Industry;
  • Quality Assurance System of the manufacturer of the starting material;
  • Manufacturing conditions under which the starting material is produced and controlled;
  • Nature of the starting material and the medicinal products in which it will be used;
  • Starting materials coming from a single product manufacturer or plant;

Starting materials coming directly from a manufacturer or in the manufacturer’s sealed container where there is a history of reliability and regular audits of the manufacturer’s Quality Assurance system being conducted by the purchaser (the manufacturer of the medicinal product) or by an officially accredited body.

The EU Annex 8 also explained cautions that it is improbable that a procedure could be satisfactorily validated for:

  • Starting materials supplied by intermediaries such as brokers where the source of manufacture is unknown or not audited;
  • Starting materials for use in parenteral products.

Similar requirements are explained in PICS guideline, Annex-8, https://picscheme.org/docview/4102.

Furthermore, according to the EU guidance, the sample to be selected should be representative. The number of samples to be taken to prepare a representative sample should be determined statistically and specified in a sampling plan. The composite sample should be homogeneous.

According to the Code of Federal Regulations (CFR), Title 21, Volume 4 (Revised as of April 1, 2020), Part 211, Current Good Manufacturing Practice for Finished Pharmaceuticals requirement of incoming material sampling and testing described under Section 211.84, “Testing and approval or rejection of components, drug product containers, and closures” – each lot of components, drug product containers, and closures shall be withheld from use until the lot has been sampled, tested, or examined, as appropriate, and released for use by the quality control unit. The CFR section does not mandate to collect samples from 100% containers for identification test but, representative samples of each shipment of each lot shall be collected for testing or examination. The number of containers to be sampled and the amount of material shall be selected based upon appropriate criteria such as statistical criteria for component variability, confidence levels, and degree of precision desired, the past quality history of the supplier, and the quantity needed for analysis and reserve where required by § 211.170.

According to Good manufacturing practices guide for drug products GUI-0001, Date issued: July 1, 2020, Date implemented: July 1, 2020, “Test a representative sample of each lot of raw material fully against specifications, using a statistically valid plan. Your sampling plan should be properly justified and based on a quality risk management principle”.

The guideline also says that “Instead of testing each container for identity, you may test only a proportion of the containers, as long as there is evidence to ensure that no single container of raw material has been incorrectly labeled”. Unlike EU GMP, Health Canada also has specified criteria to implement a reduced sampling approach by satisfying the guidance requirement and applying a quality risk management tool.

https://www.canada.ca/content/dam/hc-sc/documents/services/drugs-health-products/compliance-enforcement/good-manufacturing-practices/guidance-documents/gmp-guidelines-0001/gui-0001-eng.pdf

Australian Therapeutic Goods Administration (TGA) also detailed requirements for starting material that “a plan for reduced sampling and testing once an approved supplier has been qualified”.

https://www.tga.gov.au/publication/sampling-and-testing-listed-and-complementary-medicines

World Health Organization (WHO) Technical Report Series, No. 929, 2005, Annex 4 – “WHO guidelines for sampling of pharmaceutical products and related materials” specifies three types of sampling. According to the guidance, the sampling plan’s choice should always consider the specific objectives of the sampling and the risks and consequences associated with inherent decision errors. The guidance species following three plans:

  • The “n plan” when the material to be sampled is considered uniform and is supplied from a recognized source. n = 1 + Sqrt N (N = Number of sampling units).
  • The “p plan” when the material is uniform, is received from a recognized source and the main purpose is to test for identity. p = 0.4 Sqrt N.
  • The “r plan” when the material is suspected to be non-uniform and/or is received from a source that is not well known. r = 1.5 Sqrt N.

https://www.who.int/medicines/areas/quality_safety/quality_assurance/GuidelinesSamplingPharmProductsTRS929Annex4.pdf?ua=1

To comply with pharmacopeia is very important, and an identification test is necessary for each incoming material. Alternatively, a quick and easy method of identification is available and also described in the pharmacopeia.

The United States Pharmacopeia (USP) and Ph. Eur. provided chapters for NIR and Raman spectroscopy as methods for identity testing.

  • EDQM, “2.2.40. Near-infrared Spectroscopy,” European Pharmacopoeia 10.0.
  • EDQM, “2.2.48. Raman Spectroscopy,” European Pharmacopoeia 10.0.
  • USP, General Chapter <1119>, “Near-infrared Spectroscopy”.
  • USP, General Chapter <1120>, “Raman Spectroscopy”.

As per EU Annex 8 of the GMP guideline, the identity of a complete batch of starting materials can typically only be ensured if individual samples are taken from all the containers, and an identity test is performed on each sample. Simultaneously compliance to pharmacopeia is also mandatory; however, pharmacopeia does not indicate the sampling method and number of containers to be tested.

In such circumstances, according to EMA, it is permissible to perform identity testing on a statistically representative composite sample when this is supplemented by NIR analysis on every container. For more details of NIR one can refer EMA guidance, https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-use-near-infrared-spectroscopy-pharmaceutical-industry-data-requirements-new-submissions_en.pdf.

FDA and Health Canada also accept identification testing on composite samples with specific conditions specified in the guidance as explained in this article. For Testing of Glycerin for Diethylene Glycol, the FDA and EMA mandate testing each container for identity and the limit test for diethylene glycol.

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/testing-glycerin-diethylene-glycol

Preparation of the composite samples: EU Annex 8 suggests using representative composite samples for testing other than identification testing. However, details are not provided regarding the number of sample containers to be considered for the composite sample. Guidance regarding the preparation of composite samples depending on the number of containers is detailed in Health Canada guidance.

USP also describes the preparation of composite samples of powder starting material. Reference: USP, General Chapter <1097>, “Bulk Powder Sampling Procedures”

It is the general expectation that the composite sample should be representative of the entire lot and should be homogenous.

When there is a high risk during samplings such as Biological Drug Substances, or Aseptically filled substance, 100% sampling pose a risk. European biopharmaceutical enterprises published A Risk-Based Approach to Identity Sampling of Biological Drug Substances. For aseptically filled substances, a similar approach can be adopted considering the similarity in complexity of sampling. The 100% sampling of containers of biological products or aseptically filled material introduces two significant risks to product quality and safety.

  • Biologics has risk of increased aggregation or demixing during freezing and thawing, and an additional (unnecessary) significant stress for the therapeutic protein.
  • Sampling every aseptically-filled bulk drug substance or material container increases the risk of microbial contamination from the sampling operation. Although suitable aseptic techniques such as sampling under laminar flow, the use of single-use sterilized sampling components cannot exclude the risk of contamination and the risk of failing container-closure integrity.

https://www.efpia.eu/media/413357/01-ebe-position-paper_-id-sampling-of-biologics-ds-final_-20191015.pdf

Practical approach to the implementation of reduced sampling

When understanding various regulations and guidelines, performing identification testing and sampling of each container is a highly acceptable approach; however, reduced efforts for sampling can be implemented with scientifically sound justification and using quality risk management principles.

The risk-based reduced sampling approach can be implemented. While implementing a risk-based sampling procedure, the following parameters can be considered.

a. Source of incoming material

  • GMP compliance history of incoming raw materials manufacturer;
  • Robust Quality Assurance system of the manufacturer of the starting material;
  • Manufacturing conditions under which the starting material is produced and controlled;
  • Nature of the starting material and the medicinal products in which it will be used;
  • Starting materials coming from a single product manufacturer or plant;
  • Starting materials come directly from a manufacturer or in the manufacturer’s sealed container with a history of reliability;
  • Regular audits of the manufacturer’s Quality Assurance system are conducted by the purchaser (the medicinal product manufacturer) or by an officially accredited body;
  • Robust supply chain traceability;
  • Robust program to qualify manufacturer and supplier of incoming material;
  • Supply of incoming material form same organization’s same or another facility.

b. Quality Risk Management

  • Documented Quality Risk Management with a mitigation strategy.
  • Identify all possible failure modes, potential reasons, and review the current control to detect and/ or prevent the failure. Develop a mitigation control strategy where controls are not in place or available controls are insufficient to mitigate risks.
  • Implement the control strategy through the quality management system by revising the procedures for sampling, incoming material supplier qualification, and audit program, periodic reviews, material receipt procedures, statistical approach to evaluate incoming material quality, and adequate quality agreement between material manufacturer, supplier, and purchaser of incoming material.

c. Hybrid approach of sampling

  • A hybrid approach can be implemented for sampling, which would align with the regulation and guidance. Identification of all the incoming material containers of each lot can be done using NIR or Raman spectroscopy. Composite samples can be prepared using a risk-based approach, and pharmacopoeial identification test can be done on composite samples to comply with the pharmacopoeial monograph.
  • Before the implementation of identification of all the containers using NIR or Raman spectroscopy, comparative evaluation of pharmacopoeial method and NIR or Raman method for statistically significant lots should be done to provide sufficient evidence that the alternative method of identification is robust.

d. “Travel samples” or “Piggy-back samples” or “Satellite samples” or “Side samples”  

  • A scientifically sound, controlled, risk-based approach for identification can be implemented for biological drug substances or aseptically filled drugs without mandating 100% container-wise sampling and testing. Instead, alternative procedures such as Travel samples” or “Piggy-back samples”, or “Satellite samples” or “Side samples” can be implemented where the material manufacturing site sends samples together with the material shipment that represents an entire lot of material and transportation conditions.

Reduced testing/ skip lot or periodic testing

Reduced testing, skip lot, or periodic testing of incoming materials (Active Pharmaceutical Ingredients (API), excipients, and other raw materials) can be an acceptable approach in the pharmaceutical industry. However, the risk-based selection and frequency are key elements of implementing a compliant reduced testing, skip lot or periodic testing program. In addition, the program must necessarily be supported based on the implied regulations and suggested guidelines applicable for the country of marketing authorization.

The term periodic or skip testing means the performance of specified tests for release on pre-selected batches and/or at predetermined intervals, rather than on a batch-to-batch basis with the understanding that those batches not being tested still must meet all acceptance criteria established for that material.

https://www.ema.europa.eu/en/documents/scientific-guideline/ich-q-6-test-procedures-acceptance-criteria-new-drug-substances-new-drug-products-chemical_en.pdf

The “reduced testing” means testing of few parameters of the specification instead of performing all parameters to decide the disposition of starting materials. In such cases, the test results of those parameters for which testing has not been done may be considered from the certificate of analysis from the material manufacturer. This approach is well-established in the pharmaceutical industry, where a strong suppliers’ qualification system is implemented. According to 21 CFR 211.84(d), “(1) At least one test shall be conducted to verify the identity of each component of a drug product” and “(2) Each component shall be tested for conformity with all appropriate written specifications for purity, strength, and quality. In lieu of such testing by the manufacturer, a report of analysis may be accepted from the supplier of a component, provided that at least one specific identity test is conducted on such component by the manufacturer, and provided that the manufacturer establishes the reliability of the supplier’s analyses through appropriate validation of the supplier’s test results at appropriate intervals”.

According to FDA and EMA, guideline on Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances following texts are provided in the text.

3.1 Specifications: Definition and Justification

3.1.1 Definition of Specifications: A specification is a list of tests, references to analytical procedures, and appropriate acceptance criteria that are numerical limits, ranges, or other criteria for the tests described. It establishes the criteria to which a new drug substance or new drug product should conform to be considered acceptable for its intended use. “Conformance to specifications” means that the drug substance and/or drug product, when tested according to the listed analytical procedures, will meet the listed acceptance criteria. Specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities as conditions of approval.

It is possible that, in addition to release tests, a specification may list in-process tests as defined in section 2.3, periodic or skip tests, and other tests that are not always conducted on a batch-by-batch basis. In such cases, the applicant should specify which tests are routinely conducted batch by batch and which tests are not, with an indication and justification of the actual testing frequency. The drug substance and/or drug product should meet the acceptance criteria if tested in this situation.  It should be noted that changes in the specification after approval of the application may need prior approval by the regulatory authority.

3.1.2 Justification of Specifications When a specification is first proposed, justification should be presented for each procedure and each acceptance criterion included. The justification should refer to relevant development data, pharmacopeial standards, test data for drug substances and drug products.

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q6a-specifications-test-procedures-and-acceptance-criteria-new-drug-substances-and-new-drug-products

As per European Medicines Agency, May 2000, CPMP/ICH/367/96 ICH Topic Q 6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances, following texts are described.

2.1. Periodic or skip testing: Periodic or skip testing is the performance of specified tests at release on pre-selected batches and / or at predetermined intervals, rather than on a batch-to-batch basis with the understanding that those batches not being tested still must meet all acceptance criteria established for that product. This represents a less than full testing schedule and should therefore be justified and presented to and approved by the regulatory authority prior to implementation. This concept may be applicable to, for example, residual solvents and microbiological testing, for solid oral dosage forms. It is recognized that only limited data may be available at the time of submission of an application (see section 2.5). This concept should, therefore, generally be implemented post-approval. When tested, any failure to meet acceptance criteria established for the periodic test should be handled by proper notification of the appropriate regulatory authority(ies). If these data demonstrate a need to restore routine testing, then batch by batch release testing should be reinstated.

The ISO 2959-3 from the International Organization for Standardization (ISO) describes the skip lot sampling approach.

The ISO 2859 specifies generic skip-lot sampling procedures for acceptance inspection by attributes. The purpose of these procedures is to reduce the inspection effort on products of high quality submitted by a supplier with a satisfactory quality assurance system and effective quality controls. The reduction in inspection effort is achieved by determining at random, with a specified probability, whether a lot presented for inspection will be accepted without inspection. This procedure extends the principle of the random selection of sample items already applied in ISO 2859-1 to the random selection of lots.

The skip-lot sampling procedures specified in this part of ISO 2859 are applicable to, but not limited to, an inspection of

a) End items, such as complete products or sub-assemblies,

b) Components and raw materials, and

c) Materials in process.

ICH Q6 recommends that the reduced testing should not be implemented before the market authorization is granted.

As per ICH Q7, “Supplier approval should include an evaluation that provides adequate evidence (e.g., past quality history) that the manufacturer can consistently provide material meeting specifications. Complete analyses should be conducted on at least three batches before reducing in-house testing. However, as a minimum, a complete analysis should be performed at appropriate intervals and compared with the certificates of analysis. In addition, reliability of certificates of analysis should be checked at regular intervals.”

As per Health Canada, Good manufacturing practices guide for drug products, GUI-0001, July 1, 2020, “full confirmatory testing of the first three lots of each raw material received from a vendor, and after any significant change to the manufacturing process”.

Practical approach to the implementation of reduced testing, skip lot or periodic testing

Reduced testing, skip lot, or periodic testing is an important and commonly discussed concept for the purpose of cost and effort saving in the pharmaceutical industry. This approach reduces the testing burden by eliminating specific testing or testing batches based on predefined frequency, which could be decided based on scientific sound justification and using quality risk management principle. Regulatory guidelines discussed in previous sections also support the implementation of reduced testing, skip lot, or periodic testing.

The following parameters can be considered while implementing risk-based reduced testing or skip lot testing procedures while performing quality risk management. These are the key points that should be taken into consideration while implementation of reduced testing, skip lot or periodic testing:

  • Aim for reduced testing from product development using the Quality by Design approach;
  • Leverage the guidelines to develop quality risk management documents to produce a scientifically sound justification to implement reduced testing;
  • Develop robust vendor (Material manufacturer and supplier) qualification program;
  • Use of historical data along with a statistical evaluation to determine the probability of risk;
  • Robust control strategy for ongoing monitoring to prevent out-of-control situation along the way.

Let’s understand each one in detail.

a. Robust product development process using quality by design approach

Quality by design (QbD) is a concept first developed by the quality expert Reference: Dr. Joseph M. Juran. Juran, J.M. (1992). Juran on Quality by Design: The New Steps for Planning Quality into Goods and Services. Free Press.

According to Dr. Juran, quality should be built into a product. Sufficient knowledge should be acquired during development using the QbD approach. In the pharmaceutical industry, typical QbD elements include

(i) Define Quality Target Product Profile (QTPP);

(ii) Determine Critical Quality Attributes (CQAs);

(iii) Link Raw Material Attributes and Process Parameters to CQAs and perform Risk Assessment;

(iv) Develop a Design Space;

(v) Design and Implement a Control Strategy;

(vi) Manage Product Lifecycle with Continual Improvement.

In order to implement reduced testing of starting materials, the most essential phase to be focused on is to establish linkage between critical material attributes (CMAs), Critical Process Parameters (CPPs), and Critical Quality Attributes (CQAs). Using this information, perform a Quality Risk Assessment. Based on the Quality Risk Assessment, develop a control strategy that includes specifications for the drug substance and excipient. Quality Risk Assessment will help determine which test parameters are essential for the product, which could significantly impact product quality, and which parameter carries minimum risk. Based on the risk associated with the test parameters, the number of tests, frequency of tests can be decided. No risk or low-risk material attribute can be analyzed with less frequency. Some of the test parameters can be initially analyzed to gather sufficient information to establish a trend. Based on the trend analysis, testing can be eliminated or can be done with reduced frequency.

b. Regulatory guidance

We have discussed various guidelines in the previous section, which define the concept of skip (or periodic) testing and scenarios in which it can be implemented. Following is the compiled list of these guidelines. ICH Topic Q 6 A: Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances, published by European Medicines Agency in May 2000, document No. CPMP/ICH/367/96 and published by FDA.gov in December 2000.

  • 21 CFR PART 211 – Current Good Manufacturing Practice For Finished Pharmaceuticals, Subpart E: Control of Components and Drug Product Containers and Closures, Sec. 211.84 Testing and approval or rejection of components, drug product containers, and closures.
  • The ISO 2959-3 from the International Organization for Standardization (ISO) describes the skip lot sampling approach.
  • ICH Q7.
  • Health Canada, Good manufacturing practices guide for drug products, GUI-0001.

c. Source of incoming material

The firm’s quality system to develop and monitor the material manufacturer and supplier plays a vital role in assuring the quality of incoming materials. When a firm develops confidence in the incoming material supply that material supply is with consistent quality, regulatory compliance status is with low risk, and the failure rate is low, it gives a positive sign for implementation of reduced testing. Following are vital components that should be considered while implementing the reduced testing.

  • GMP compliance history of the incoming raw materials manufacturer;
  • Robust Quality Assurance system of the raw material manufacturer;
  • Manufacturing conditions under which the starting material is produced and controlled;
  • Nature of the starting material and the medicinal products in which it will be used;
  • Starting materials coming from a single product manufacturer or plant;
  • Starting materials come directly from a manufacturer or in the manufacturer’s sealed container with a history of reliability;
  • Regular audits of the manufacturer’s Quality Assurance system are conducted by the purchaser (the medicinal product manufacturer) or by an officially accredited body;
  • Robust supply chain traceability;
  • A robust program to qualify manufacturers and supplier of incoming material.

d. Historical data and statistics

It is not necessary that the reduced testing, skip-lot testing, or periodic testing can be implemented only for new products where an extensive amount of product development work has been done. For the legacy products or the products developed in the recent past where the QbD approach might not be used during product development can also undergo reduced testing, skip lot testing, or periodic testing programs. 

In such a scenario, historical data should be collected to understand the consistency of incoming material quality. This can be done using control charts and calculating test parameters’ process performance index and process capability index.

The number of batches to be considered for statistical evaluation should be statistically significant to provide a reasonable estimate of types of variations. The control chart should be prepared separately for each attribute to carry out a statistical assessment. The following criteria can be considered while performing the statistical assessment.

Statistical evaluation using control chart of material attributes

Control charts will provide excellent insight about variability in the data. It provides information about common-cause of variation and special-cause of variation. Batch-to-batch common cause of variations should be minimum. Any special cause of variation should be identified and attended at the time of notice, and appropriate corrective and preventive actions should be in place to prevent the source of such variations. All such special causes of variability should be taken care of before implementing a reduced testing program to eliminate chances of failure and surprises. Control charts can be interpreted with visual observations as well as using Nelson rules.

There are eight rules to interpret the control charts. These rules are also called Nelson rules. These rules were published in the October 1984 issue of the Journal of Quality Technology in an article by Lloyd S Nelson. Interpretation of out of control for non-random situations can be done as follows.

RuleDescription
1Any one point is > 3 SD from the average (Beyond Zone A). This means the point is Out of Trend (OOT)
29 (or >) points consecutively are on the same side of the average. Some continued bias happens. (In or beyond Zone C). This means the average is probably changed.
36 (or >) points consecutively are progressively increasing or decreasing. A trend exists. This test indicates a drift in the process average. Such drift could be resulted because of wear and tear, maintenance issues, improvement in skill, etc.
414 (or >) points consecutively alternating up and down, increasing then decreasing. This pattern specifies that 2 systematically alternating causes are producing different results. This could happen while using two alternate suppliers, monitoring quality for two different or alternating shifts. The fluctuation is beyond the noise.
52 (or 3) out of 3 points consecutively are > 2 SD from the average in the same direction (In Zone A or beyond). This is the signs early warning of process shift.
64 (or 5) out of 5 points consecutively are > 1 SD from the average in the same direction (Zone B or beyond). Similar to the above point, this is an early warning indicator for potential process shift. There is a strong propensity for samples to be slightly out of control.
715 points consecutively are all within 1 SD of the average on either side of the mean (within Zone C). This indicates a smaller variation than expected.
88 points consecutively exist, but none within 1 SD of the average, and the points are in both directions from the average (Within Zone B or A or beyond). This specifies that different samples are affected by different factors. This could happen if different samples in a chart were produced by 1 of 2 different machines, where one produces above average and the other below.

Reference:https://tech-publish.com/annual-product-quality-review-apqr/

Statistical evaluation using process performance index (Ppk) and process capability index (Cpk) of material attributes

When Ppk and Cpk are comparable (approximately 20% of each other), it implies that there is minimal special-cause of variation in the process. Therefore, all the observed variability represents the common-cause of variation. When Ppk measure is greater than 1.5, it indicates an approximate failure rate of 3.4 in 1 million. When Ppk higher than 1.5, difference between the Ppk and Cpk to be accepted, dependent on the probability of the special-cause of variation.

Y = A X (B/C)

Y = Probability of test attribute fall outside the specification limit

A = Probability Out of Specification (OOS) for test parameter

B/C = Frequency of skipping test (Example: When testing is done for the test at every 100 batches, B/C = 99/100)

Source: https://www.europeanpharmaceuticalreview.com/

 

e. Ongoing control strategy and mitigation plan

The frequency of skip lot testing should be carefully decided based on the frequency of batches produced at the manufacturing site. Frequency should be decided in such a way that there should be early detection and control so as to ensure a lower risk to the patient.

There is low risk in implementing reduced testing when finished dosage formulation is analyzed without any reduced testing or skip lot testing and test parameter of finished product testing is directly representing the critical material attributes of starting material.

Additionally, comparative evaluation of historically produced test data of incoming material should be done with material manufacturers’ data. When the test data of incoming material and test data from material manufacturers’ certificate of analysis is analytically equivalent, it signals the reliability of material manufacturers’ testing.

When reduced testing or skip lot testing is implemented for incoming material, results of test parameters should be considered from the material manufacturer’s certificate of analysis. The test results of the material manufacturer should be formally reviewed for every incoming lot before approval of the lot for its use in the formulation.

In case of any confirmed out-of-specification result observed for incoming material, reduced testing or skip lot testing should be temporarily suspended. Risk assessment for the previously used incoming material should be performed to ensure the patient safety aspect. During the risk assessment, testing of previously used material should be considered. Risk assessment should at least include the number of batches received after the last successful testing of incoming material to the last incoming material for which out-of-specification results were observed.

f. Implementation of Process Analytical Technology (PAT)

As per the US FDA PAT guideline, “today significant opportunities exist for improving pharmaceutical development, manufacturing, and quality assurance through innovation in product and process development, analysis, and process control”.

FDA also says that “the agency considers PAT to be a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes, to ensure final product quality”. Using PAT tools, the significant effort can be reduced in terms of testing the incoming material. For example, regulators expects identification of 100% incoming containers, which can be achieved using tools such as Near infra-red spectroscopy (NIR) or  Raman spectroscopy with much less effort than traditional methods.

g. Quality Risk Management

  • Documented Quality Risk Management with a mitigation strategy.
  • Identify all possible failure modes, potential reasons, and review the current control to detect and/ or prevent the failure. Develop a mitigation control strategy where controls are not in place, or available controls are insufficient to mitigate risks.
  • Implement the control strategy through the quality management principle by revising the procedures for sampling, incoming material supplier qualification and audit program, periodic reviews, material receipt procedures, statistical approach to evaluate incoming material quality, and adequate quality agreement between material manufacturer, supplier, and purchaser of incoming material.

Regulatory approvals for implementation of reduced testing, skip lot or periodic testing

Reduced testing, skip lot or periodic testing can be implemented for starting material based on scientific sound rationale, applying quality risk management principles, and by preparing Standard Operating Procedure that can be reviewed by regulatory agency during inspection.

Implementation of reduced testing, skip lot testing, or periodic testing is a GMP aspect and it may be governed using Standard Operating Procedures and may not require regulatory filing. Again it is depending on what has been written in the filed specification. In case it is explicitly specified the frequency of testing and number of test to be done routinely, it is prudent to implement the reduced testing, skip lot testing, or periodic testing through regulatory updates. Even if the requirement is not specifically addressed in the specification, organization to organization, approach for implementation may vary; some may implement through procedural change only and some may want to file update to regulatory agency.

For US market, Relaxing an acceptance criterion or deleting a test for raw

materials used in drug substance manufacturing, in-process materials prior to the final intermediate, starting materials introduced prior to the final drug substance intermediate, or drug substance intermediates considered as moderate change and documentation approach would be Changes Being Effected 30 days (CBE30) filing.

In the case of the EU market, implementation of reduced testing, periodic testing, or skip lot testing is categorized as a type-IA variation. Therefore, the applicant can proceed with the annual report submission. As per EMA recommendations, Type IA variations do not require approval by the authorities before their implementation by the holder. However, within 12 months from the implementation date, the holder must submit simultaneously to all national competent authorities. It needs to be stressed that if the competent authority rejects the variation, the holder would immediately stop implementing the concerning variations.

Observation cited by regulatory agencies for inadequately implementation of reduced testing, skip lot or periodic testing

While implementing the reduced testing, skip lot testing or periodic testing, utmost care should be taken. It requires data accuracy, scientifically sound quality risk management, and regulatory guideline references. Since the quality of starting material may impact product quality, inadequate implementation of reduced testing, skip lot, or periodic testing may result in regulatory citation during the inspection. Following are few examples of regulatory citations.

Example: 1

“Test results from component suppliers are accepted without testing each component according to the established specification without evaluating the reliability of the supplier’s analyses.

Specifically, full testing for (b)(4) is not performed; an identity test is performed with all other testing accepted from the supplier’s Certificate of Analysis (COA). There is no procedure for performing reduced testing to require an initial assessment of the reliability of the supplier’s COA, and verification of the

supplier’s COA at appropriate intervals. (b)(4) is used during the commercial manufacture of (b)(4) and uncoated (b)(4) granules”.

Reference: https://www.fda.gov/media/87661/download

Above example provides clarity that firm had no procedure for performing reduced testing to require an initial assessment of the reliability of the supplier’s COA, and verification of the supplier’s COA at appropriate intervals.

Example: 2

“You do not have data to support reduced testing for genotoxic and other impurities. During process validation for (b)(4) you committed to testing the final API validation batches for elemental impurities and residual solvents (b)(4). After the three (b)(4) validation batches you test (b)(4) batches (b)(4) for elemental impurities and residual solvents. During process validation for (b)(4) you tested the finished API validation batches for potential genotoxic impurity (b)(4). After the validation batches you test (b)(4) for potential genotoxic impurity genotoxic impurity”.

Reference: https://www.fda.gov/media/117875/download

Above example provides information that firm might not have data to support reduced testing for genotoxic and other impurities.

References:

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