GXP

GXP Talk - Question #79: Are Contract Manufacturers Responsible for Preparing the Annual Product Quality Review?

“GXP Talk” provides a forum for addressing compliance issues identified by readers of the Journal of GXP Compliance.

“GXP Talk” is the longest running continuing series in the Journal of GXP Compliance.  A total of 77 questions on GXP topics have been previously discussed.  We discuss #78 and #79 this issue.  Previous discussions have addressed a wide range of compliance activities covering essentially all sections of the US GMPs.  Responses to questions and associated opinions have been contributed by representatives from multiple pharmaceutical industries and regulatory agencies.  In the current format, questions and answers are presented together.

Readers are invited to participate ad contribute questions, answers, and discussion for this series – please share your successful practices with other readers.  This column succeeds when we are able to address current GXP issues submitted by interested readers.  Please contact column coordinators Jerry Lanese at jerry@lanesegroup.com or Rich Poska at richposka@gmail.com with comments, or submissions for publication.  We welcome your input.

QUESTION #79

My firm is a contract manufacturer.  Our clients are constantly telling us that we must prepare the Product Review for them.  Who is responsible for the preparation of the Product Review?

ANSWER

This is probably one of the most frequently asked questions that relates to the Annual Product Review that must be prepared for each drug product manufactured or marketed by a firm.  When the product is entirely produced in one facility, the responsibility for preparing the Annual Product Review is clear.  It should be prepared by an individual or group in that facility; this responsibility typically falls to Quality Assurance.  The problem surfaces when a virtual organization markets the product and activities required to achieve a finished distributed product are contracted out to various organizations that can be located throughout the country or throughout the world.  In this case the preparation of the Product Quality Review becomes complex and can be a challenge.  No one really wants to take on the task; unless the responsibility is specifically assigned to an organization, it does not get done.  The answer depends on what organization holds the license for the product and what agreements are in place covering the various activities required for the production, quality control, and distribution of the product.

Terminology

In order to resolve the issue, we should review terminology.  What is this report called?  I have already used two terms to identify the report:  Annual Product Review and Product Quality Review.  The requirement for an annual review of the documentation for each product can be found in the United States GMP 211.180(e)  which states:

Written records required by this part shall be maintained so that data therein can be used for evaluating, at least annually, the quality standards of each drug product to determine the need for changes in drug product specifications or manufacturing or control procedures.

One must keep in mind that these words were finalized in 1978 when the current GMPS were released.  Between 1978 and approximately 2000, this report was referred to as the Annual Product Review by the industry.  Then, after the turn of the century, as the industry began hearing reference to Quality Systems, the FDA published two Quality System-based inspectional guidances ,   which referred to this report as the Product Review; this term is used in US guidance.

Since that time a number of global GMPs have been published.  These documents use “Product Quality Review” as their preferred terminology.  A partial list of regional GMPs and report names is presented in the following table.

 

REGION

GMP TITLE

EFFECTIVE DATE

PRODUCT REPORT TITLE

United States

21CFR211.180(e)

Good Manufacturing Practices for Pharmaceutical Products

1979

Product Review

CPGM 7356.002

2001/2017

Product Review

CPGM 7345.848

2001/2010

Product Review

 

ICH Q7

GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS

2001

Quality Review

EU

EudraLex The Rules Governing Medicinal Products in the European Union EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use

2004/2005/

2010

Product Quality Review

Canada

Good manufacturing practices guide for drug products (GUI-0001)

2017

Annual Product Quality Review

PIC/S

Pharmaceutical Inspection Convention/Pharmaceutical Inspection Cooperation Scheme PIC/S

2017

Product Quality Review

WHO

WHO Good Manufacturing Practices for Pharmaceutical Products

 

Product Quality Review

China

China CFDA (now NMPA) Medical Device and Pharmaceutical Regulations

2017

Product Quality Review

Japan

GMP Guideline for Pharmaceutical Products

 

Product Quality Review

 

There is no statement in the US regulation or inspectional guidances that identifies what individual or organization is responsible for the preparation of the Product Quality Review.  This is no real surprise since the pharmaceutical industry had not been impacted by virtual operations in 1978 when the GMPs were written and there had been no significant impact on the production of pharmaceutical products by virtual organizations by 2001 when the system based inspectional guidances were implemented.  However, in many of the other countries and regions, the regulatory bodies were starting from scratch in the development of their respective regulations and they had some foresight into the impact of virtual operations on the pharmaceutical industry.  Also, it would appear that many of the countries or regions are more flexible than the United States. and they have released revisions to earlier GMPS that have reflected doing business in the contemporary virtual arena.  Therefore, in order to find a contemporary answer to the question, “who is responsible for the preparation of the Product Review or Product Quality Review,” one has to reference other regulations for guidance; these do not provide a totally consistent message.

Additional Terminology

Before referencing regulations from other areas, it is necessary to understand some additional terminology.

License holder.  This is a term used mainly in the United States that refers to the organization that holds the regulatory authorization giving permission to market a drug product. The license holder is the organization that holds the NDA or ANDA.

Marketing Authorisation Holder.  A Marketing Authorisation Holder (MAH) is a term used in jurisdictions around the world that identifies the company, firm or non-profit organisation that has been granted a marketing authorisation. The marketing authorisation allows the holder to market a specific medicinal product, in one or more EU member states or other jurisdictions.    The Marketing Authorization holder is synonymous with the license holder.

Technical Agreement.  A Technical Agreement (also known as a Quality Agreement) is a written contract that is required whenever a company is outsourcing an activity covered by the Good Manufacturing Practice ("GMP") Guidelines.  It sets out the GMP responsibilities of each of the parties. 

Regulatory Guidance

Examples of the limited world-wide guidance on who should write the Product Quality Review include a statement found in both the European Union  and WHO GMPs .

Where marketing authorization holder is not the manufacturer, there should be a technical agreement in place between the various parties that defines their respective responsibilities in producing the Product Quality Review.

The WHO GMP7 offers an additional statement on who is responsible for making sure the product quality review is prepared.

The authorized person responsible for batch certification, together with the marketing authorization holder, ensure that the quality review is performed in a timely manner and is accurate.

Canada identifies the responsibility for the preparation of the Annual Product Quality Review .

The Quality Control Department of the importer or distributor should ensure that the Annual Product Quality Review is performed in a timely manner.

Both of the statements identify who should ensure that the report is prepared.  This is not necessarily the preparer.

A statement found in The European Union6 and WHO7 GMPs clearly states who should prepare the Product Quality Review. Although this requirement is not legally binding in the United States it does give the United States audience some guidance on the management of the Product Quality Review program and the mechanism for identifying that responsibility.

There should be a technical agreement, or quality agreement, in place between the various parties that defines their respective responsibilities in producing the product quality review.

Interpretation

We can interpret these statements and statements found in other GMPs to help answer our question.  When an organization contracts any part of the production and control of a product it should have a Quality Agreement or Technical Agreement in place with each contracting organization involved in the production and control that identifies what organization is responsible complying with each GMP requirement.  The GMP requirement that is the focus of this discussion is the Product Quality Review.  Therefore, the organization that holds the license and is contracting any part of the production and control should have a Technical (Quality) Agreement with all of the contractors that are performing any production and control activities.  This agreement should define responsibilities.  Specific to this discussion, it should identify what organization is responsible for the preparation of the Product Quality Review and the review due dates.  It may not be that simple.  The organization that would most likely be responsible for the Product Quality Review preparation is the contractor responsible for production because it has the production related data including in-process control data, deviations, non-conformances, changes to the process and other production specific data.  Another source of key information is the contract laboratory.  That organization should be responsible for providing the Quality Control information.  It is likely that information required for the preparation of the Product Quality Review will be generated and maintained by a number of contractors.  The Technical Agreement should clearly identify what contractor organization is responsible for the preparation of the Product Quality Review and when the Product Quality Review is due, what data is required from each of the contractors, and when it is due to the organization responsible for the preparation of the overall report.

The statements in the regulations cited above indicate that within a given organization the responsibility for the preparation of the Product Quality Review falls on the Quality Unit.

If the various production and control activities are contracted to a number of organizations, it is the responsibility of the license holder (Marketing Authorization holder) to define, in technical agreements, which contractor is responsible for the preparation of the Product Quality Review, what data should be provided by other contractors and a time line for providing data to the preparer and completion of the report. 

If someone asks, “Who is responsible for the preparation of the Product Quality Report?” it is a clear indication that responsibilities are not clearly defined.  For a virtual operation, the Technical (Quality) Agreement should define all responsibilities related to the production and control of a product, including the preparation of the Product Quality Review.

References

  1. United Stages Good Manufacturing Practices for Finished Pharmaceuticals; 21CFR 211.180(e)
  2. US FDA.  CPG 7356,002; 2001, 2017
  3. USFDA CPG 7345.848; 2001
  4. European Patients’ Academy.  Marketing Authorization Holder (MAH).  www.eupati.eu/glossary/marketing-authorisation-holder/    accessed 3/11/19
  5. GMP Quality/Technical Agreements.  TaylorWessing Synapse.  https://united-kingdom.taylorwessing.com/synapse/may14.html, accessed 3/11/19.
  6. EudraLex.  Rules Governing Medicinal Products in the European Union;  Volume 4, EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use; Chapter 1,  Pharmaceutical Quality System.
  7. WHO Good Manufacturing Practices for Pharmaceutical Products: Main Principles; https://www.who.int/medicines/areas/quality_safety/quality_assurance/TRS... accessed 3/14/19.
  8. Good Manufacturing Practices Guide for Drug Products (GUI-0001). https://www.canada.ca/en/health-canada/services/drugs-health-products/co... accessed 3/14/19



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