Pharmaceuticals in general not only produce drugs but they also produce tons of data. Regulatory agencies across the globe insist on generation of data for each and every activity. We should understand that there is value in data generation. Data is generated automatically when we follow GMP regulations.

Significant amount of data is generated when we are operating a pharmaceutical firm as per norms. This data may include the dossiers of product development, purchase of raw material, manufacturing, packaging, testing, QMS, stability, sale and distribution and what not. This data is used for evaluating the quality standards of each drug product

Product Quality Review (PQR) is one such documentation exercise which helps to assess the quality of each pharmaceutical product. PQR is not only a regulatory requirement but it helps to critically review the issues or problems associated with the product. It helps the firm in continuous improvement.

Now, we would like to understand the concept of PQR by the popular concept of 5W and 1H.

What is Product Quality Review (PQR)?

Product quality review may be defined as regular, periodic or rolling quality reviews of all drug products being manufactured by a firm. This includes domestic as well as export-only products.

Why to conduct Product Quality Review (PQR)?

The PQR when conducted diligently helps to assess the overall healthiness of the product being manufactured. The PQR shall be conducted to highlight any overall trends and to identify product/process improvements. This can be done by verifying and identifying:

  • the consistency of the existing process(es);
  • trends in product data;
  • the appropriateness of current specifications for starting materials, intermediates and finished products;
  • to verify compliance of the registered particulars of pharmaceutical products (Marketing Authorization);
  • deficiencies not detected by routine testing, monitoring or performance metrics; and
  • identify opportunities for product and process improvements,

The goals of the annual assessments are to:

  • Confirm that the products and associated processes remain in a state of control.
  • Identify the need for changes to the products or processes.
  • Recognize opportunities for continuous improvement.

When to conduct PQR?

PQR shall be carried out based on the risk assessment associated with the product and process. However, the same shall not be later than a year i.e. it shall be carried out on annual basis. The products manufactured in the previous years shall be included in the PQR. Some regulators like EUGMP insists on including the data from previous review periods also.

Who to conduct PQR?

Quality Manager along with the cross functional team shall collect, collate, assess, analyze, interpret and conclude the PQR. The report thus prepared shall be reviewed by various stakeholders and shall be reviewed by Quality Assurance Head.

What are the limits for the minimum and maximum number of batches to be included in a PQR?

There is no limit for the maximum number of batches to be included in the PQR. More the Merrier! However, real challenge is when the number of batches are too low. If very few batches (for example, less than three) are manufactured within a year, a PQR could be conducted every two years. In this case the justification should also consider the risk associated with the type of medicine and should be documented. Also, product review from previous years shall be taken inro account while preparing PQRs.

What are the factors that may require frequent preparation of PQR?

As mentioned earlier, PQR shall be prepared on the basis of risk. While assessing the risk special consideration shall be given to products with a history of recurring deviations on critical parameters. Also, the products undergoing frequent recalls and returns, receiving regular complaints and undergoing frequent process changes shall be evaluated on more regular basis.

What is grouping of products for PQR? How to group the products?

Drug products can be grouped by a particular characteristic or type while preparation of PQR. The product groupings must be scientifically justified. The grouping and the reason for doing so shall be justified in detail in the PQR procedure or report itself. Grouping shall never be done on the basis of commercial factors.

Products selected within a group must be similar enough so that the parameters being reviewed in the PQR are representative of the group. Every batch in a group shall be reviewed.

Acceptable Grouping: The grouping of products on the basis of the same dosage form containing the same or very similar active ingredients and excipients, and manufactured using the same type of equipment and process. Examples:

  1. Same ingredients and primary packaging, but different strengths
  2. Same presentations but different pack size or different brand name
  3. Products to be marketed in different regions.

Unacceptable Grouping: The grouping of products having significantly different excipients, chemical/physical interactions, different type of equipment or process used to manufacture etc. is unacceptable. Examples:

  1. Drug product with same APIs but different excipient
  2. Different formulation Tablet vs Capsule vs Syrup
  3. Products manufactured with wet granulation vs dry granulation, coated vs uncoated tablets

How to conduct PQR? What is the difference between the requirements of various regulators w.r.t. PQR elements?

The basic requirement before conducting PQR is to have a detailed written procedure for carrying out the PQR. The firm must form a cross functional team to collect, collate, assess, analyze, interpret and conclude the PQR. The report thus prepared shall be reviewed by various stakeholders and shall be reviewed by Quality Assurance Head. The report must include summary conclusions on the quality of the product and any corrective/preventive actions initiated and/or completed during the review period. The PQR has a strong link to a firm’s corrective and preventive action (CAPA) program, and any identified CAPA items should be tracked appropriately and completed in a timely fashion.

Various elements of PQR required as per various regulatory agencies are as follows:

S. No. Parameters USFDA EU PIC/s WHO
1

Representative number of batches, whether approved or rejected

 M – – –
2 Product complaints M M M M
3 Recalls M M M M
4 Returned or salvaged drug products M M M M
5 Investigations M M M M
6 Deviations or non-conformances D M M M
7

In-process and finished product testing results and a discussion of any adverse trending

 D M M M
8

Product stability results and a discussion of any adverse trending

 D M M M
9

Changes to process that occurred during the review period

 D M M M
10

Starting materials and packaging materials used for the product, especially those from new sources and in particular the review of supply chain traceability of active substances

 – M M M
11

All batches that failed to meet established specification(s) and their investigation

 D M M M
12

Marketing authorization variations submitted, granted, or refused, including those for export only

 – M M M
13

Adequacy of any other previous corrective actions on product processes or equipment

 – M M M
14

Post-market commitments for new marketing authorizations or variations to marketing authorizations

 – M M M
15

Qualification status of relevant equipment and utilities

 – M M M
16 Contractual arrangements – M M M
17 Salvaged products – D D D

*Key – M:Mandatory, D:Desirable

 

As a part of continuous improvement, additional data elements may need to be included in the review process. Firms should assess all of the data that are gathered throughout their operations and shall include the relevant information.

 

How USFDA requirements of PQR are different from the requirements of EU, PIC/S and WHO?

Although, more or less the requirements are same of various regulatory agencies, however there are few differences which are mentioned below:

  • EU, PIC/S and WHO explicitly require an assessment of the results of the review to determine whether corrective or preventive actions are needed, or whether revalidation is required. Although FDA expects firms to perform this type of analysis, but the same is not explicit mentioned in the CFR. We have seen many USFDA 483s issued on inadequate PQR.
  • EU, PIC/S and WHO require the assessment of current data against data from previous reviews in an attempt to identify adverse trends. USFDA does not require firms to look at data from previous review periods.
  • EU, PIC/S and WHO allows grouping of products, however, USFDA does not allow such grouping. PQR must be carried out on individual products.
  • EU, PIC/S and WHO do not specify a requirement for a written procedure that outline the PQR process. USFDA requirement for a written procedure that outlines the PQR process.
  • As explained above, EU, PIC/S and WHO include a number of parameters which is not required by USFDA regulations.

 

What are the examples of information to be reviewed while assessing various parameters?

S. No. Parameters Examples
1

Starting materials: A review of starting materials including packaging materials used in the product, especially those from new sources and in particular the review of supply chain traceability of active substances

i.    Identify all starting and packaging materials received in the year and used in product manufacture

ii.    Name of the suppliers/manufacturers of the materials

iii.    Supplier’s Certificate of Analysis (CoA)

iv.    Significant deviations or trends

v.    Inspection rejection rate

vi.    Changes to production process or specifications by suppliers

vii.    Results of analytical tests
2

In­process controls and quality control testing: A review of critical in-process controls and finished product results

Trend in­-process test results and QC test results in the manufacturing and packaging process from both chemistry and microbiology aspects:

Trending may take into consideration:

Physical variations – e.g. weight/dimension, friability, hardness, disintegration time, fill volume/overage, uniformity of content

Chemical variations – e.g. assay, related substances/manufacturing related ­impurities, pH, residual solvents

Rejected units – e.g. breakages, particulates, etc.

Yield reconciliation from stages of the manufacturing process using data from the associated batch records
3

Manufactured batches (intermediates, bulk, finished products and campaign batches): A review of all batches that failed to meet established specification(s) and their investigation

List deviations and non­-conformances associated with the product under review.

Identify current status of investigations and summarize reason for the failure and their investigation, completed investigations, corrective actions taken and effectiveness of the action
4

Deviations and CAPA: A review of all significant deviations or non-conformances, their related investigations, and the effectiveness of resultant corrective and preventive actions taken

A.    List the following relating to significant deviations and non-conformances

–        reason for the failure

–        completed investigations

–        corrective actions taken

B.    Assess corrective actions for significant deviations and non-conformances from previous PQRs, indicating the status of each of the corrective actions, and their effectiveness
5

Process or testing changes: A review of all changes carried out to the processes or analytical methods

i.          Changes assessed should consider both those closed during the review period and approved to commence but not yet implemented. The change status should be identified e.g. approved to commence and closed

ii.          Categorize the change type e.g. component, labelling packaging materials, manufacturing process, analytical methods etc. and assess for trends and overall impact on quality

iii.          Identify the batches affected

iv.          Provide a justification for the change

v.          Review the effectiveness/impact of the change on the batch under review
6

Marketing Authorizations: A review of Marketing Authorization variations submitted, granted or refused, including those for third country (export only) dossiers

i.          number of products submitted and granted/refused

ii.          number of products registers locally and overseas

iii.          any changes made to the product that require submission of a variation to the Marketing Authorization

iv.          for the above, variations that have been submitted. If not submitted, the reasons therefore should be investigated and a conclusion documented

v.          for variations submitted, whether or not they have been granted or refused. If refused, the impact should be assessed and documented
7

Stability programme: A review of the results of the stability monitoring programme and any adverse trends

i.          List the number of batches of product in review included in stability studies during the review period

ii.          review the results of any long term and on­going stability of the bulk and marketed product

iii.          Include product information such as manufacturing date, reference to the associated method, shelf ­life, etc.

iv.          Review any out­ of ­specification results
8

Returned product: A review of all quality-related returns and the investigations performed at the time

i.          Batch number(s)

ii.          Reason for return and classification of reason for trending

iii.          Associated investigation report number

iv.          Actions taken and batches affected
9

Complaints and/or adverse events: A review of all quality-related complaints and the investigations performed at the time

i.          Batch number(s)

ii.          Reason for complaint and classification for trending

iii.          Previous instances over a designated time period

iv.          Associated investigation report number

v.          Actions taken and batches affected

vi.          Current status
10

Recalls: A review of all quality-related recalls and the investigations performed at the time

i.          Batch number(s)

ii.          Reason for complaint and classification for trending

iii.          Regulator(s) notified and required regional responses

iv.          Associated investigation report number

v.          Actions taken and batches affected

vi.          Current status
11

Review of past PQR responses: A review of adequacy of any other previous product process or equipment corrective actions

The focus of this requirement is on previous PQRs and the status and effectiveness of associated actions:

i.          review and report on previous PQR CAPAs and change implementation status

ii.          assess effectiveness of actions taking into account the current PQR findings
12

Post­-marketing commitments: For new Marketing Authorizations and variations to Marketing Authorizations, a review of post-marketing commitments

 i.          Country of commitment

ii.          Product name and presentation

iii.          Description of the commitment

iv.          Status of the commitment
13

Equipment qualification: The qualification status of relevant equipment and utilities, e.g. HVAC, water, compressed gases, etc.

List and review the following for critical equipment/instruments and utilities in production and laboratory departments associated with the product in review:

i.          Qualification/re­qualification status and the next qualification due date of equipment used in the production processes and QC laboratory

ii.          Reference to relevant qualification reports

iii.          Review changes made to equipment and utilities which resulted in re­qualification and assess for subsequent impact to product quality
14

Contractual agreements: A review of any contractual arrangements to ensure that they are up to date

 Review contracts for services associated with the product in review and report:

i.          name and address of the contract acceptor

ii.          availability and details of the written contract

iii.          type of service provided e.g. testing or maintenance and calibration services

iv.          confirmation that the services provided are aligned with the marketing authorization

 

Why to evaluate PQR results?

The PQR results must be evaluated to determine whether any steps shall be required to keep the process and other parameters in a state of control. Some of the actions include:

  1. corrective or preventive actions;
  2. validation or re­validation; and
  3. other site or process changes.

It shall be understood that all the processes should be demonstrated to be in control by determining upper/lower limits and trends. Preventive actions must be implemented for any processes showing lesser control before any deviations or OOS happens.

References:

  1. WHO TRS 986 Annexure 2
  2. PIC/S Guide to Good Manufacturing Practice for Medicinal Products Part I, PE009-14
  3. Volume 4, EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, Chapter 1, Pharmaceutical Quality System
  4. US Food and Drugs Administration 21CFR 211.180